Novel cyclohexyl sulphones

ABSTRACT

Novel sulphones of formula I are disclosed:  
                 
The compounds modulate the processing of amyloid precursor protein by gamma-secretase, and hence are useful in the treatment or prevention of Alzheimer&#39;s disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation under 35 U.S.C. §120 of U.S. patentapplication Ser. No. 11/261,365, which is a continuation under 35 U.S.C.§ 120 of U.S. patent application Ser. No. 10/223,993, filed Aug. 20,2002, now U.S. Pat. No. 6,984,663, which claims priority under 35 U.S.C.§119(a) of Great Britain application no. 0120347.0, filed Aug. 21, 2001,and International application no. PCT/GB01/03741, filed Aug. 21, 2001.

BACKGROUND OF THE INVENTION

The present invention relates to a novel class of compounds, theirsalts, pharmaceutical compositions comprising them, processes for makingthem and their use in therapy of the human body. In particular, theinvention relates to novel sulphones which modulate the processing ofAPP by γ-secretase, and hence are useful in the treatment or preventionof Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent form of dementia.Although primarily a disease of the elderly, affecting up to 10% of thepopulation over the age of 65, AD also affects significant numbers ofyounger patients with a genetic predisposition. It is aneurodegenerative disorder, clinically characterized by progressive lossof memory and cognitive function, and pathologically characterized bythe deposition of extracellular proteinaceous plaques in the corticaland associative brain regions of sufferers. These plaques mainlycomprise fibrillar aggregates of β-amyloid peptide (Aβ), and althoughthe exact role of the plaques in the onset and progress of AD is notfully understood, it is generally accepted that suppressing orattenuating the secretion of Aβ is a likely means of alleviating orpreventing the condition. (See, for example, ID research alert 19961(2):1-7; ID research alert 1997 2(1):1-8; Current Opinion in CPNSInvestigational Drugs 1999 1(3):327-332; and Chemistry in Britain,January 2000, 28-31.)

Aβ is a peptide comprising 39-43 amino acid residues, formed byproteolysis of the much larger amyloid precursor protein. The amyloidprecursor protein (APP or AβPP) has a receptor-like structure with alarge ectodomain, a membrane spanning region and a short cytoplasmictail. Different isoforms of APP result from the alternative splicing ofthree exons in a single gene and have 695, 751 and 770 amino acidsrespectively.

The Aβ domain encompasses parts of both extra-cellular and transmembranedomains of APP, thus its release implies the existence of two distinctproteolytic events to generate its NH₂— and COOH-termini. At least twosecretory mechanisms exist which release APP from the membrane andgenerate the soluble, COOH-truncated forms of APP (APPs). Proteaseswhich release APP and its fragments from the membrane are termed“secretases”. Most APPs is released by a putative α-secretase whichcleaves within the Aβ domain (between residues Lys¹⁶ and Leu¹⁷) torelease α-APP_(S) and precludes the release of intact Aβ. A minorportion of APP_(S) is released by a β-secretase, which cleaves near theNH₂-terminus of Aβ and produces COOH-terminal fragments (CTFs) whichcontain the whole Aβ domain. Finding these fragments in theextracellular compartment suggests that another proteolytic activity(γ-secretase) exists under normal conditions which can generate theCOOH-terminus of Aβ.

It is believed that γ-secretase itself depends for its activity on thepresence of presenilin-1. In a manner that is not fully understoodpresenilin-1 appears to undergo autocleavage.

There are relatively few reports in the literature of compounds withinhibitory activity towards β- or γ-secretase, as measured in cell-basedassays. These are reviewed in the articles referenced above. Many of therelevant compounds are peptides or peptide derivatives.

SUMMARY OF THE INVENTION

The present invention provides a novel class of non-peptidic compoundswhich are useful in the treatment or prevention of AD by modulating theprocessing of APP by the putative γ-secretase, thus arresting theproduction of Aβ.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound of formula I:

wherein:

m is 0 or 1;

Z represents halogen, CN, NO₂, N₃, CF₃, OR^(2a), N(R^(2a))₂, CO₂R^(2a),OCOR^(2a), COR^(2a), CON(R^(2a))₂, OCON(R^(2a))₂, CONR^(2a)(OR^(2a)),CON(R^(2a))N(R^(2a))₂, CONHC(═NOH)R^(2a), heterocyclyl, phenyl orheteroaryl, said heterocyclyl, phenyl or heteroaryl bearing 0-3substituents selected from halogen, CN, NO₂, CF₃, OR^(2a), N(R^(2a))₂,CO₂R^(2a), COR^(2a), CON(R^(2a))₂ and C₁₋₄alkyl;

R^(1b) represents H, C₁₋₄alkyl or OH;

R^(1c) represents H or C₁₋₄alkyl;

with the proviso that when m is 1, R^(1b) and R^(1c) do not bothrepresent C₁₋₄alkyl;

Ar¹ represents C₆₋₁₀aryl or heteroaryl, either of which bears 0-3substituents independently selected from halogen, CN, NO₂, CF₃, OH,OCF₃, C₁₋₄alkoxy or C₁₋₄alkyl which optionally bears a substituentselected from halogen, CN, NO₂, CF₃, OH and C₁₋₄alkoxy;

Ar² represents C₆₋₁₀aryl or heteroaryl, either of which bears 0-3substituents independently selected from halogen, CN, NO₂, CF₃, OH,OCF₃, C₁₋₄alkoxy or C₁₋₄alkyl which optionally bears a substituentselected from halogen, CN, NO₂, CF₃, OH and C₁₋₄alkoxy;

R^(2a) represents H, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₆alkyl,C₂₋₆alkenyl, any of which optionally bears a substituent selected fromhalogen, CN, NO₂, CF₃, OR^(2b), CO₂R^(2b), N(R^(2b))₂, CON(R^(2b))₂, Arand COAr; or R^(2a) represents Ar; or two R groups together with anitrogen atom to which they are mutually attached may complete anN-heterocyclyl group bearing 0-4 substituents independently selectedfrom ═O, ═S, halogen, C₁₋₄alkyl, CN, NO₂, CF₃, OH, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, CO₂H, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,carbamoyl, Ar and COAr;

R^(2b) represents H, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₆alkyl,C₂₋₆alkenyl, any of which optionally bears a substituent selected fromhalogen, CN, NO₂, CF₃, OH, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, CO₂H, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, carbamoyl, Ar and COAr; or R^(2b)represents Ar; or two R^(2b) groups together with a nitrogen atom towhich they are mutually attached may complete an N-heterocyclyl groupbearing 0-4 substituents independently selected from ═O, ═S, halogen,C₁₋₄alkyl, CN, NO₂, CF₃, OH, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, CO₂H,amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, carbamoyl, Ar and COAr;

Ar represents phenyl or heteroaryl bearing 0-3 substituents selectedfrom halogen, C₁₋₄alkyl, CN, NO₂, CF₃, OH, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,carbamoyl, C₁₋₄alkylcarbamoyl and di(C₁₋₄alkyl)carbamoyl;

“heterocyclyl” at every occurrence thereof means a cyclic or polycyclicsystem of up to 10 ring atoms selected from C, N, O and S, wherein noneof the constituent rings is aromatic and wherein at least one ring atomis other than C; and

“heteroaryl” at every occurrence thereof means a cyclic or polycyclicsystem of up to 10 ring atoms selected from C, N, O and S, wherein atleast one of the constituent rings is aromatic and wherein at least onering atom of said aromatic ring is other than C;

or a pharmaceutically acceptable salt thereof.

Where a variable occurs more than once in formula I or in a substituentthereof, the individual occurrences of that variable are independent ofeach other, unless otherwise specified.

As used herein, the expression “C_(1-x)alkyl” where x is an integergreater than 1 refers to straight-chained and branched alkyl groupswherein the number of constituent carbon atoms is in the range 1 to x.Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl andt-butyl. Derived expressions such as “C₂₋₆alkenyl”, “hydroxyC₁₋₆alkyl”,“heteroaryl”C₁₋₆alkyl, “C₂₋₆alkynyl” and “C₁₋₆alkoxy” are to beconstrued in an analogous manner.

The expression “C₃₋₆cycloalkyl” as used herein refers to nonaromaticmonocyclic or fused bicyclic hydrocarbon ring systems comprising from 3to 6 ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cyclohexenyl.

The expression “C₃₋₆ cycloalkylC₁₋₆alkyl” as used herein includescyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl andcyclohexylmethyl.

The expression “C₆₋₁₀aryl” as used herein includes phenyl and naphthyl.Phenyl is preferred.

The expression “heterocyclyl” as used herein means a cyclic orpolycyclic system of up to 10 ring atoms selected from C, N, O and S,wherein none of the constituent rings is aromatic and wherein at leastone ring atom is other than carbon. Preferred heterocyclyl groupscontain 3-7 ring atoms, most preferably 4-6 ring atoms. Examples ofheterocyclyl groups include azetidinyl, pyrrolidinyl, tetrahydrofuryl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, imidazolidinyl,oxazolidinyl, thiazolidinyl, 2,5-diazabicyclo[2.2.1]heptyl,2-aza-5-oxabicyclo[2.2.1]heptyl and 1,4-dioxa-8-azaspiro[4.5]decanyl.Unless otherwise indicated, heterocyclyl groups may be bonded through aring carbon atom or a ring nitrogen atom where present. “C-heterocyclyl”indicates bonding through carbon, while “N-heterocyclyl” indicatesbonding through nitrogen.

The expression “heteroaryl” as used herein means a cyclic or polycyclicsystem of up to 10 ring atoms selected from C, N, O and S, wherein atleast one of the constituent rings is aromatic and comprises at leastone ring atom which is other than carbon. Where a heteroaryl ringcomprises two or more atoms which are not carbon, not more than one ofsaid atoms may be other than nitrogen. Preferred heteroaryl groupscontain 5 or 6 ring atoms in total. Examples of heteroaryl groupsinclude pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furyl,thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, oxadiazolyl, triazolyl and thiadiazolyl groups andbenzo-fused analogues thereof. Further examples of heteroaryl groupsinclude tetrazole, 1,2,4-triazine and 1,3,5-triazine.

The term “halogen” as used herein includes fluorine, chlorine, bromineand iodine, of which fluorine and chlorine are preferred.

For use in medicine, the compounds of formula I may advantageously be inthe form of pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds of formula I or of theirpharmaceutically acceptable salts. Suitable pharmaceutically acceptablesalts of the compounds of this invention include acid addition saltswhich may, for example, be formed by mixing a solution of the compoundaccording to the invention with a solution of a pharmaceuticallyacceptable acid such as hydrochloric acid, sulphuric acid,benzenesulphonic acid, methanesulphonic acid, fumaric acid, maleic acid,succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid,tartaric acid, carbonic acid or phosphoric acid. Alternatively, wherethe compounds of the invention carry an acidic moiety, pharmaceuticallyacceptable salts may be formed by neutralisation of said acidic moietywith a suitable base. Examples of pharmaceutically acceptable salts thusformed include alkali metal salts such as sodium or potassium salts;ammonium salts; alkaline earth metal salts such as calcium or magnesiumsalts; and salts formed with suitable organic ligands, such as aminesalts (including pyridinium salts) and quaternary ammonium salts.

Where the compounds according to the invention have at least oneasymmetric centre, they may accordingly exist as enantiomers. Where thecompounds according to the invention possess two or more asymmetriccentres, they may additionally exist as diastereoisomers. It is to beunderstood that all such isomers and mixtures thereof in any proportionare encompassed within the scope of the present invention.

Regardless of the presence or absence of asymmetric centres, certaincompounds in accordance with the invention may exist as enantiomers byvirtue of the asymmetry of the molecule as a whole. It is to beunderstood that in such cases both enantiomers, and mixtures thereof inany proportion, are included within the scope of the invention, and thatstructural formulae depicting molecules of this type shall berepresentative of both of the possible enantiomers, unless otherwiseindicated.

In the compounds of formula I, Ar¹ typically represents optionallysubstituted phenyl or heteroaryl. Typical heteroaryl embodiments of Ar¹include optionally substituted pyridyl, in particular optionallysubstituted 3-pyridyl. Ar¹ is preferably selected from phenyl groupssubstituted in the 4-position with halogen, methyl or trifluoromethyl,and phenyl groups substituted in the 3- and 4-positions by halogen. In apreferred embodiment of the invention Ar¹ represents 4-chlorophenyl. Inanother preferred embodiment Ar¹ represents 4-trifluoromethylphenyl.

Ar² is typically selected from phenyl groups substituted in the 2- and5-positions by halogen. In a preferred embodiment of the invention, Ar²represents 2,5-difluorophenyl.

In a particular embodiment, Ar¹ is 4-chlorophenyl or4-trifluoromethylphenyl and Ar² is 2,5-difluorophenyl.

R^(1b) typically represents H, methyl or OH, preferably H.

R^(1c) typically represents H or methyl, preferably H.

Z is typically selected from CN, N₃, OR^(2a), N(R^(2a))₂, CO₂R^(2a),COR^(2a), CON(R^(2a))₂, OCON(R^(2a))₂, CONR^(2a)(OR^(2a)),CON(R^(2a))N(R^(2a))₂, and optionally substituted phenyl or heteroaryl.

In one embodiment of the invention m is 0. In an alternative embodimentof the invention m is 1. Aptly, m is 1.

When m is 1 and R^(1b) is OH, Z preferably represents optionallysubstituted phenyl or heteroaryl.

Particular values of R^(2a) include H, aryl (such as phenyl), heteroaryl(such as pyridyl), C₃₋₆cycloalkyl (such as cyclopropyl, cyclobutyl andcyclopentyl), C₃₋₆cycloalkylC₁₋₆alkyl (such as cyclopropylmethyl),C₂₋₆alkenyl (such as allyl), and linear or branched C₁₋₆alkyl which isoptionally substituted with CF₃, Ar, OR^(2b), N(R^(2b))₂, CO₂R^(2b) orCON(R^(2b))₂.

Examples of N-heterocyclyl groups represented by N(R^(2a))₂ includepiperidin-1-yl (optionally substituted with OH, CO₂H, CO₂C₁₋₄alkyl, Meor Ph), piperazin-1-yl (optionally substituted with Me or Ph),morpholin-4-yl, thiomorpholin-4-yl, 1,1-dioxo-thiomorpholin-4-yl,2-oxo-imidazolidin-1-yl, 5,5-dimethyl-2,2-dioxo-oxazolidin-3-yl,2,5-dioxo-imidazolidin-1-yl, 2-oxo-oxazolidin-3-yl, 2-oxo-pyridin-1-yl,and 2-oxo-pyrrolidin-1-yl.

R^(2b) typically represents H or C₄alkyl.

When Z represents OR^(2a), R^(2a) aptly represents H, Ar (especiallyheteroaryl such as pyridyl), alkyl (such as methyl, ethyl, propyl orbutyl), or substituted alkyl (especially CH₂Ar such as benzyl orpyridylmethyl).

When Z represents N(R^(2a))₂, the R^(2a) groups aptly complete anN-heterocyclyl group which is optionally substituted as described above.Preferred substituents include ═O and methyl. Specific examples ofN-heterocyclyl groups represented by Z include succinimidyl,morpholin-4-yl, 2-oxo-imidazolidin-1-yl,5,5-dimethyl-2,2-dioxo-oxazolidin-3-yl, 2,5-dioxo-imidazolidin-1-yl,2-oxo-oxazolidin-3-yl, 2-oxo-pyridin-1-yl, and 2-oxo-pyrrolidin-1-yl.

When Z represents CO₂R^(2a), R^(2a) aptly represents H or alkyl (such asmethyl, ethyl, propyl or butyl). In a preferred embodiment of theinvention, Z represents CO₂H or a pharmaceutically acceptable saltthereof.

When Z represents COR^(2a), R^(2a) aptly represents Ar, especiallyheteroaryl, and in particular 5-membered heteroaryl such as1,2,4-triazol-3-yl.

When Z represents CON(R^(2a))₂ or OCON(R^(2a))₂, the R^(2a) groupsindependently represent H or optionally substituted alkyl, cycloalkyl,cycloalkylalkyl or alkenyl, or together complete an N-heterocyclylgroup. Very aptly, one R^(2a) represents H and the other representsalkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,tert-butyl or 1-ethylpropyl), alkenyl (such as allyl), cycloalkyl (suchas cyclopropyl, cyclobutyl or cyclopentyl), cycloalkylalkyl (such ascyclopropylmethyl) or substituted alkyl (such as alkyl substituted withAr, especially 2-pyridylethyl, 3-(imidazol-1-yl)propyl or 2-phenylethyl;or alkyl substituted with CF₃, CO₂R^(2b), or CON(R^(2b))₂, especially2,2,2-trifluoroethyl, methoxycarbonylmethyl or carbamoylmethyl).Alternatively, the two R^(2a) groups complete an N-heterocyclyl group,such as morpholine, thiomorpholine, thiomorpholine-1,1-dioxide,4-methylpiperazine, 4-phenylpiperazine, piperidine, 4-hydroxypiperidineor piperidine which is substituted in the 3- or 4-position withCO₂R^(2b) and/or C₁₋₄alkyl, especially 3- or 4-carboxypiperidine, 3- or4-ethoxycarbonylpiperidine, 3-carboxy-3-methylpiperidine and3-ethoxycarbonyl-3-methylpiperidine.

When Z represents CONR^(2a)(OR^(2a)), each R^(2a) aptly represents H oralkyl, such as methyl.

When Z represents CON(R^(2a))N(R^(2a))₂, each R^(2a) aptly represents Hor alkyl. Specific examples include CONHNH₂ and CONHNH^(t)Bu.

When Z represents CONHC(═NOH)R^(2a), R^(2a) aptly represents alkyl suchas methyl or ethyl.

Heteroaryl groups represented by Z are very aptly 5-membered, such astetrazole, triazole, thiazole, thiadiazole, oxadiazole, pyrazole andimidazole, which are typically unsubstituted or substituted with methylor hydroxy groups. The keto-tautomers of hydroxy-substituted heteroarylgroups are to be considered interchangeable with the enol forms.Specific examples include 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-2-yl,1,2,3,4-tetrazol-5-yl, 3-hydroxy-1,2,4-triazol-5-yl, 1,2,4-triazol-3-yl,5-methyl-1,2,4-triazol-3-yl, 2,5-dimethyl-1,2,4-triazol-3-yl,1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl,5-methyl-1,3,4-thiadiazol-2-yl, 3-methyl-1,2,4-oxadiazol-5-yl,imidazol-2-yl, imidazol-1-yl, 4-methylthiazol-2-yl, pyrazol-1-yl,1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, and 1,2,3-triazol-2-yl.

Examples of individual compounds in accordance with formula I areprovided in the Examples section appended hereto.

The compounds of formula I have an activity as modulators of theprocessing of APP by γ secretase.

The invention also provides pharmaceutical compositions comprising oneor more compounds of formula I or the pharmaceutically acceptable saltsthereof and a pharmaceutically acceptable carrier. For use in saidcompositions, compounds of formula I which comprise a carboxylic acidgroup are preferably in the form of the free acid or the sodium saltthereof. Preferably these compositions are in unit dosage forms such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, transdermal patches, auto-injector devices or suppositories;for oral, parenteral, intranasal, sublingual or rectal administrationr,or for administration by inhalation or insufflation. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums or surfactants such assorbitan monooleate, polyethylene glycol, and other pharmaceuticaldiluents, e.g. water, to form a solid preformulation compositioncontaining a homogeneous mixture of a compound of the present invention,or a pharmaceutically acceptable salt thereof. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulationcomposition is then subdivided into unit dosage forms of the typedescribed above containing from 0.1 to about 500 mg of the activeingredient of the present invention. Typical unit dosage forms containfrom 1 to 250 mg, for example 1, 2, 5, 10, 25, 50, 100, 200 or 250 mg,of the active ingredient. The tablets or pills of the novel compositioncan be coated or otherwise compounded to provide a dosage form affordingthe advantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, poly(vinylpyrrolidone) or gelatin.

The present invention also provides a compound of formula I or apharmaceutically acceptable salt thereof for use in a method oftreatment of the human body. Preferably the treatment is for a conditionassociated with the deposition of β-amyloid. Preferably the condition isa neurological disease having associated β-amyloid deposition such asAlzheimer's disease.

The present invention further provides the use of a compound of formulaI or a pharmaceutically acceptable salt thereof in the manufacture of amedicament for treating or preventing Alzheimer's disease.

The present invention further provides a method of treatment of asubject suffering from or prone to a condition associated with thedeposition of β-amyloid which comprises administering to that subject aneffective amount of a compound according to formula I or apharmaceutically acceptable salt thereof. Preferably the condition is aneurological disease having associated β-amyloid deposition such asAlzheimer's disease.

For treating or preventing Alzheimer's Disease, a suitable dosage levelis about 0.01 to 250 mg/Kg per day, preferably about 0.10 to 100 mg/Kgper day, especially about 1.0 to 50 mg/Kg, and for example about 10 to30 mg/Kg of body weight per day. Thus, a dose of about 500 mg per personper day may be considered. The compounds may be administered on aregimen of 1 to 4 times per day. In some cases, however, dosage outsidethese limits may be used.

Compounds of formula I in which m is 0 and Z is CO₂R^(2a), CON(R^(2a))₂,CONR^(2a)(OR^(2a)), CON(R^(2a))N(R^(2a))₂ or CONHC(═NOH)R^(2a) may beprepared by coupling of a carboxylic acid (1) with (respectively)R^(2a)OH, HN(R^(2a))₂, HNR^(2a)(OR^(2a)), HN(R^(2a))N(R^(2a))₂ orH₂NC(═NOH)R^(2a),

where Ar¹, Ar², R^(1c) and R^(2a) have the same meanings as before. Anyof the standard coupling techniques may be used, including the use ofcoupling agents such as dimethylaminopyridine, hydroxybenzotriazole,dicyclohexylcarbodiimide, carbonyldiimidazole and the like. In onepreferred method, the acid is converted to the corresponding acidchloride (e.g. by treatment with oxalyl chloride in DMF solution) andreacted directly with the desired nucleophile. In another preferredmethod, the acid is converted to an active ester derivative such as thepentafluorophenol ester (e.g. by coupling with the phenol in thepresence of dicyclohexyl carbodiimide), and this intermediate is reactedwith the desired nucleophile.

The acids (1) are available by hydrolysis of the esters (2), typicallyunder alkaline conditions such as treatment with LiOH in ethanolsolution:

where R² represents alkyl such as methyl or ethyl, and Ar¹, Ar² andR^(1c) have the same meanings as before.

The esters (2) are available by reduction of the alkylidene derivatives(3), optionally followed by alkylation with (C₁₋₄alkyl)-L where L is aleaving group (especially bromide or iodide) when R^(1c) is other thanH:

where Ar¹, Ar² and R² have the same meanings as before. The reductionmay be carried out using sodium borohydride and nickel(II) chloride inethanol, while the optional alkylation may be effected by treating theester (2, R^(1c)=H)) with strong base (e.g. sodiumbis(trimethylsilyl)amide) in an aprotic solvent at low temperature,followed by treatment with (C₁₋₄alkyl)-L and warming to roomtemperature.

If desired, the unsaturated esters (3) may be hydrolysed to thecorresponding acids and converted to amides by reaction with HN(R^(2a))₂prior to reduction of the olefinic bond.

The unsaturated esters (3) are available from condensation of a ketone(4) with Ph₃P═CHCO₂R²:

where Ar¹, Ar² and R² have the same meanings as before, while theketones (4) are available by decarboxylation of the enols (5), which inturn are formed by reaction of a sulphone (6) with at least twoequivalents of an acrylate (7):

where Ar¹, Ar² and R² have the same meanings as before. Thedecarboxylation may be accomplished by heating at 150° C. in DMSO in thepresence of sodium chloride and water, while reaction of (6) with (7)may be carried out at ambient temperature in an inert solvent such asTHF in the presence of strong base such as potassium t-butoxide.

Alternatively, the ketones (4) may be prepared by reaction of vinylsulphones (6a) with 2-trimethylsilyloxybutadiene:

where Ar¹ and Ar² have the same meanings as before. The reaction may becarried out by heating the reactants at 130° C. in xylene, thenhydrolysing the resulting silyl enol ether with aqueous acid. The vinylsulphones (6a) may be prepared by reaction of benzyl sulphones (6) withN,N,N′,N′-tetramethyldiaminomethane and acetic anhydride in DMF at 60°C.

The sulphones (6) are prepared by oxidation of thioethers Ar²-CH₂—SAr¹(8), which in turn are formed by reaction of thiols Ar¹SH (9) withbenzyl derivatives Ar²CH₂-L (10), where L is a leaving group such aschloride or bromide and Ar¹ and Ar² have the same meanings as before.The reaction between (9) and (10) takes place in an inert solvent suchas dichloromethane in the presence of a base such as triethylamine, oralternatively in aqueous alcoholic solution in the presence of alkalisuch as sodium hydroxide. The oxidation of (8) to (6) is convenientlyeffected by m-chloroperoxybenzoic acid in an inert solvent such asdichloromethane, or alternatively by hydrogen peroxide in awater-toluene mixture in the presence of sodium tungstate and a phasetransfer catalyst.

Compounds of formula I in which m is 0 and Z is COR^(2c) may be preparedby treatment of the corresponding compounds in which Z isCONR²C(OR^(2c)) with R^(2c)—Li, where R^(2c) represents R^(2a) which isother than H. The reaction is typically carried out in an aproticsolvent at low temperature, and is particularly useful when R^(2c) inCOR^(2c) represents aryl or heteroaryl. In such cases, subsequentreduction of the carbonyl group (e.g. using sodium borohydride) providesthe compounds of formula I in which m is 1, R^(1b) is OH and Z is arylor heteroaryl.

Compounds of formula I in which m is 0 and Z is halogen, CN, N₃,OR^(2a), N(R^(2a))₂ or heteroaryl bonded through N may be obtained byreaction of a sulphonate ester (11) with (respectively) halide ion,cyanide ion, azide ion, R^(2a)OH, HN(R^(2a))₂ or heteroaryl comprisingNH in the ring:

where L¹ represents a sulphonate leaving group (such as mesylate,tosylate or triflate) and Ar¹, Ar² and R^(2a) have the same meanings asbefore. The displacement reaction may be carried out in DMF at elevatedtemperature, e.g. about 80° C. When the nucleophile is R^(2a)OH,HN(R^(2a))₂ or heteroaryl comprising NH in the ring, it is advantageousto generate the corresponding anion by treatment with sodium hydrideprior to reaction with (11).

The sulphonates (11) are prepared by reaction of the alcohols (12) withthe appropriate sulphonyl chloride (e.g. under anhydrous conditions atlow temperature in the presence of a tertiary amine).

The alcohols (12) are available from the hydroboration of alkenes (13):

wherein Ar¹, Ar² and R^(1c) have the same meanings as before. Theprocess typically involves reaction with borane in THF at roomtemperature, followed by treatment with alkaline hydrogen peroxide andseparation of the desired cis isomer by chromatography. Alkenes (13) areavailable from ketones (4) by condensation with Ph₃P═CHR^(1c) whereR^(1c) has the same meaning as before.

An alternative route to the alcohols (12) in which R^(1c) is H involvesreduction of a ketone (4) (e.g. using borohydride) to the correspondingsecondary alcohol (14), converting said alcohol (14) to thecorresponding mesylate (or equivalent leaving group), effectingnucleophilic displacement with cyanide ion, hydrolysing the resultingnitrile to the corresponding carboxylic acid, followed by reduction tothe primary alcohol. The hydrolysis is typically carried out under acidconditions (e.g. in a mixture of acetic acid and conc. HCl at 110° C.)and the reduction is conveniently carried out by sequential treatmentwith isobutyl chloroformate and borohydride in THF.

Compounds of formula I in which m is 0 and Z is OCOR^(2a) orOCON(R^(2a))₂ are available by reaction of alcohols (12) with(respectively) R^(2a)COCl or R^(2a)—NCO in accordance with standardprocedures.

Compounds of formula I in which m is 0 and Z represents aryl orheteroaryl bonded through C may be prepared by reaction of a sulphonylderivative (11) with the appropriate aryllithium or heteroaryllithium.Alternatively, the corresponding compounds in which Z represents afunctional group such as CN, CO₂H, CONH₂, CONHNH₂ or CONHC(═NOH)R^(2a)may be converted to heteroaryl derivatives using conventional techniquesof heterocyclic synthesis. Examples of such conversions include:

treatment of a nitrile derivative with azide to form a tetrazol-5-ylderivative;

treatment of a nitrile derivative with methanol and HCl, followed by ahydrazide, to form a 5-substituted-1,3,4-oxadiazol-3-yl derivative;

treatment of a hydrazide derivative with triethylorthoformate to form a1,3,4-oxadiazol-3-yl derivative;

treatment of a hydrazide derivative with acetamidine to form a5-methyl-1,2,4-triazol-3-yl derivative;

treatment of an amide derivative with Lawesson's reagent, followed by achloromethyl ketone, to form a 4-substituted-thiazol-2-yl derivative;

treatment of a carboxylic acid derivative (or active ester thereof) withsemicarbazide to form a 1,2,4-triazol-3-one derivative;

treatment of a carboxylic acid derivative (or active ester thereof) witha hydrazide, followed by Lawesson's reagent, to form a5-substituted-1,3,4-thiadiazol-2-yl derivative; and

treatment of a CONHC(═NOH)R^(2a) derivative with strong base (e.g.potassium t-butoxide) to form a 3-substituted-1,2,4-oxadiazol-5-ylderivative.

Illustrations of these conversions are provided in the Examples appendedhereto.

Compounds of formula I in which m is 1 and R^(1b) is H or C₄alkyl may beobtained via oxidation of an alcohol (12) to the corresponding aldehydeor ketone, and elaboration of the carbonyl group thereof in the mannerdescribed previously in connection with conversion of the ketones (4)into compounds of formula I in which m is 0.

Preferred routes to the compounds of formula I in which m is 1 andR^(1b) and R^(1c) are both H involve the nitrites (14):

where Ar¹ and Ar² have the same meanings as before. The nitrites (14)are available by reaction of the sulphonates (11) in which R^(1c) is Hwith cyanide ion as described previously, or (more preferably) bycondensation of ketones (4) with diethyl (cyanomethyl)phosphonate andreduction of the resulting cyclohexylidene-acetonitriles withL-Selectride™. The condensation is typically carried out in THF at about−5° C. in the presence of potassium t-butoxide, and the reduction istypically carried out in THF at −60° C.

Reduction of nitrites (14) with diisobutylaluminium hydride (DIBAL) intoluene at −60° C., followed by acid hydrolysis, provides the aldehydes(15), which may be further reduced to the alcohols (16) using sodiumborohydride in a ethanol/toluene mixture at 4° C.:

where Ar¹ and Ar² have the same meanings as before. The alcohols (16)may be converted to the sulphonate esters (17) (where L¹ has the samemeaning as before) and thence to the nitriles (18) by the methodsdisclosed above in connection with compounds (11) and (12). The nitrites(18) may be converted to the acids (19) by acid hydrolysis or, morepreferably, by treatment with DIBAL in toluene at −60° C. followed byquenching in aqueous acid to form the homologated aldehydes (20), thenoxidation to the acids (19), e.g. using an aqueous mixture of sodiumchlorite and sulphamic acid.

Alternatively, the homologated aldehydes (20) may be obtained from thealdehydes (15) by a Wittig-type reaction with(methoxymethyl)triphenylphosphonium chloride, then hydrolysis of theresulting enol ethers with aqueous acid. The Wittig reaction may becarried out in toluene in the presence of potassium t-butoxide, whilethe hydrolysis takes place in a mixture of DMF and aqueous hydrochloricacid at ambient temperature.

The cyclohexanepropanoic acids (19) may be converted into othercompounds of formula I by routes similar to those described above inconnection with the cyclohexaneacetic acids (1).

Where they are not themselves commercially available, the startingmaterials and reagents employed in the above-described synthetic schemesmay be obtained by the application of standard techniques of organicsynthesis to commercially available materials.

It will be appreciated that many of the above-described syntheticschemes may give rise to mixtures of stereoisomers. In particular,certain products may be formed as mixtures of cis and trans isomers inwhich a particular ring substituent is on the same or opposite side ofthe ring as the arylsulphonyl group. Such mixtures may be separated byconventional means such as fractional crystallisation and preparativechromatography.

Certain compounds according to the invention may exist as opticalisomers due to the presence of one or more chiral centres or because ofthe overall asymmetery of the molecule. Such compounds may be preparedin racemic form, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution. The novel compounds may, forexample, be resolved into their component enantiomers by standardtechniques such as preparative HPLC, or the formation of diastereomericpairs by salt formation with an optically active acid, such as(−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaricacid, followed by fractional crystallization and regeneration of thefree base. The novel compounds may also be resolved by formation ofdiastereomeric esters or amides, followed by chromatographic separationand removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

An assay which can be used to determine the level of activity ofcompounds of the present invention is described in WO01/70677. Apreferred assay to determine such activity is as follows:

1) SH-SY5Y cells stably overexpressing the βAPP C-terminal fragmentSPA4CT, are cultured at 50-70% confluency. 10 mM sodium butyrate isadded 4 hours prior to plating.

2) Cells are plated in 96-well plates at 35,000 cells/well/100 L inDulbeccos minimal essential medium (DMEM) (phenol red-free)+10% foetalbovine serum (FBS), 50 mM HEPES buffer (pH7.3), 1% glutamine.

3) Make dilutions of the compound plate. Dilute stock solution 18.2× to5.5% DMSO and 11× final compound concentration. Mix compounds vigorouslyand store at 4° C. until use.

4) Add 10 μL compound/well, gently mix and leave for 18 h at 37° C., 5%CO₂.

5) Prepare reagents necessary to determine amyloid peptide levels, forexample by Homogeneous Time Resolved Fluorescence (HTRF) assay.

6) Plate 160 μL aliquots of HTRF reagent mixture to each well of a black96-well HTRF plate.

7) Transfer 40 μL conditioned supernatant from cell plate to HTRF plate.Mix and store at 4° C. for 18 hours.

8) To determine if compounds are cytotoxic following compoundadministration, cell viability is assessed by the use of redox dyereduction. A typical example is a combination of redox dye MTS (Promega)and the electron coupling reagent PES. This mixture is made up accordingto the manufacturer's instructions and left at room temperature.

9) Add 10 μL/well MTS/PES solution to the cells; mix and leave at 37° C.

10) Read plate when the absorbance values are approximately 0.4-0.8.(Mix briefly before reading to disperse the reduced formazan product).

11) Quantitate amyloid beta 40 peptide using an HTRF plate reader.Alternative assays are described in Biochemistry, 2000, 39(30),8698-8704. See also, J. Neuroscience Methods, 2000, 102, 61-68.

The Examples of the present invention all had an ED₅₀ of less than 1 μM,typically less than 0.1 μM and in many cases less than 10 nM in at leastone of the above assays.

The following examples illustrate the present invention.

EXAMPLES Intermediate 1

Method (a)

4-Chlorothiophenol (3.6 g, 0.025 mol) in dichloromethane (100 ml) wastreated with 2,5-difluorobenzyl bromide (5.17 g, 0.025 mol) andtriethylamine (3.9 ml, 0.028 mol), reaction was stirred for 2 hours thendiluted with dichloromethane (250 ml) and washed with water (100 ml) andbrine (100 ml). The separated organic layer was dried (MgSO₄) andevaporated to dryness. Product was purified by passing down a plug ofsilica eluting with hexane-ethyl acetate mixtures. 5.12 g. ¹H NMR CDCl₃7.23 (4H, s), 6.69-6.86 (3H, m) and 4.04 (2H, s).

This thioether (5.12 g, 0.018 mol) was dissolved in dichloromethane (100ml) and treated with m-chloroperoxybenzoic acid (14.3 g, 0.042 mol (50%w/w)) and stirred for 2 hours. The reaction was then washed with Na₂S₂O₅(5% solution, 100 ml), brine (50 ml), dried (MgSO₄) and evaporated todryness. The sulphone product was purified on silica eluting withhexane-ethyl acetate mixtures, 3.6 g. ¹H NMR CDCl₃ 7.61 (2H, d, J=8.6Hz), 7.45 (2H, d, J=8.6 Hz), 7.13-7.08 (1H, m), 7.05-7.00 (1H, m),6.99-6.87 (1H, m) and 4.36 (2H, s).

Method (b)

4-Chlorothiophenol (253 g, 1.75 mol) was dissolved in industrialmethylated spirits (1265 mL) and 2M sodium hydroxide solution (90 mL)was added, maintaining the temperature below 20° C. A solution of2,5-difluorobenzyl bromide (355 g, 10.72 mol) in industrial methylatedspirits (250 mL) was added dropwise to the thiolate solution,maintaining the temperature below 15° C. Upon completion of thereaction, water (1000 mL) was added. The resulting slurry was aged at 5°C. and then filtered. The cake was washed sequentially with coldindustrial methylated spirits:water (40:60) and then water (500 mL).Drying in vacuo at ambient temperature furnished2-[[(4-chlorophenyl)thio]methyl]-1,4-difluorobenzene (462.3 g, 99.6%).¹H NMR (CDCl₃)—as obtained for the corresponding intermediate of Method(a).

A mixture of sodium tungstate dihydrate (1.83 g, 5.54 mmol) as asolution in water (36.56 mL), 1M sulfuric acid (2.50 mL),2-[[(4-chlorophenyl)thio]methyl]-1,4-difluorobenzene (Example 1) (100 g,0.37 mol) and Aliquat 336™ (2.99 g, 7.39 mmol) in toluene (500 mL) washeated to 45° C., and 27.5% aqueous hydrogen peroxide (114.2 mL) wasadded slowly. The mixture was cooled and the unreacted peroxide wasquenched by addition of 20 wt % sodium metabisulfite solution (120 mL).The layers were separated. The organic phase was washed with water (190mL) and concentrated to a total volume of approximately 200 mL. Heptane(400 mL) was added and the resulting mixture was cooled to 0° C. andfiltered. The wet cake was washed with 2:1 heptane:toluene (200 mL) andthen heptane (200 mL). The product was dried in vacuo at 40° C. to yield107.6 g of 2-[[(4-chlorophenyl)sulfonyl]methyl]-1,4-difluorobenzene (96%yield). ¹H NMR CDCl₃—as obtained via Method (a).

Intermediate 2

Prepared as for Intermediate 1, using 4-trifluoromethylthiophenol, andobtained as a solid. ¹H NMR (360 MHz, CDCl₃) δ 7.85-7.83 (2H, m),7.76-7.74 (2H, m), 7.15-7.10 (1H, m), 7.06-7.0 (1H, m), 6.92-6.86 (1H,m) and 4.46 (2H, s).Preparation 1

Intermediate 1 (1 g, 3.31 mmol) and methyl acrylate (0.84 ml, 9.27 mmol)in tetrahydrofuran (30 ml) were treated dropwise with potassium^(t)butoxide (3.64 ml 1M solution in tetrahydrofuran, 3.64 mmol). Thereaction was stirred for 2 hours, diluted with ethyl acetate (100 ml)and washed with water (50 ml) and brine (50 ml). The organic phase wasseparated, dried (MgSO₄) and evaporated to dryness, and the productpurified on silica eluting with hexane-ethyl acetate mixtures.(1.0 g).¹H NMR CDCl₃ 12.0 (1H, s), 7.41 (4H, s), 7.06-7.0 (2H, m), 6.87-6.81(1H, s), 3.81 (3H, s), 3.38 (1H, dd, J=3.2, 15.8 Hz), 3.02-2.92 (2H, m),2.52 (1H, dd, J=5.7, 18.5 Hz), 2.3-2.2 (1H, m) and 2.2-2.1 (1H, m).Preparation 2

Method (a)

The ester from Preparation 1 (1.0 g, 2.25 mmol) in dimethylsulfoxide (10ml) was treated with NaCl (0.3 g, 4.96 mmol) and water (0.9 ml, 4.96mmol) and heated at 150° C. for 2 hours. The cooled reaction mixture wasdiluted with ethyl acetate (100 ml), washed with saturated NH₄Cl (100ml), and the organic phase separated, dried (MgSO₄) and evaporated todryness. The product was purified on silica eluting with hexane-ethylacetate mixtures, 0.5 g. ¹H NMR CDCl₃ 7.43-7.37 (4H, m), 7.22-7.1 (2H,m), 6.97-6.9 (1H, m), 3.05-2.98 (2H, m) and 2.61-2.53 (2H, m).

Method (b)

(i) 2-[[(4-chlorophenyl)sulfonyl]methyl]-1,4-difluorobenzene(Intermediate 1) (100 g, 0.33 mol) andN,N,N′,N′-tetramethyldiaminomethane (34.2 g, 0.50 mol) were dissolved indimethyl formamide (1000 mL) at 60° C. Acetic anhydride (68.3 g, 1.00mol) was added slowly and the reaction mixture was aged for 5 hours.Water (1000 mL) was added dropwise and the resulting slurry was cooledto 5° C. The solids were filtered, and the cake washed sequentially withdimethyl formamide:water (40:60, 200 mL) and water (500 mL). Dryingovernight in vacuo at 40° C. under a nitrogen stream furnished2-[1-[(4-chlorophenyl)sulfonyl]ethenyl]-1,4-difluorobenzene (98 g, 95%).¹H NMR (CDCl₃) 7.64-7.59 (2H, m), 7.43-7.39 (2H, m), 7.27-7.22 (1H, m),7.08-6.88 (2H, m), 6.88 (1H, s) and 6.09 (1H, s).

(ii) A solution of2-[1-[(4-chlorophenyl)sulfonyl]ethenyl]-1,4-difluorobenzene (100 g, 0.32mol) in xylenes (500 ml) was azeotropically distilled at 38° C., 20mmHg, until 300 mL solvent had been removed.2-Trimethylsilyloxybutadiene (90.4 g, 0.64 mol) was then added under anitrogen atmosphere and the mixture heated to 130° C. After the reactionwas completed, the mixture was distilled in vacuo to remove residualdiene, whilst maintaining a constant volume by the addition of xylenes(400 mL). The mixture was cooled to 50° C. and THF (500 mL) and 3M HCl(424 mL, 1.27 mol) were added. After the hydrolysis was complete, thelayers were separated. The organic layer was washed with water (300 mL)and then concentrated by atmospheric distillation until 350 mL ofsolvent had been removed. The solution was allowed to cool untilcrystallisation started, heptane (600 mL) was added and the resultingmixture cooled to ambient. The solids were filtered and washedsequentially with heptane:xylenes (3:1, 200 ml) and then heptane (200ml). Drying overnight in vacuo at 40° C. furnished4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexanone (110 g,90% yield). ¹H NMR CDCl₃— as for the product obtained via Method (a).Preparation 3

Prepared by the procedures of Preparations 1 and 2 (method (a)) usingIntermediate 2 to give the product as a solid. (0.3 g) ¹H NMR (360 MHz,CDCl₃) δ 7.71-7.69 (2H, d, J=7.5 Hz), 6.62-6.60 (2H, d, J=7.4 Hz),7.22-7.11 (2H, m), 6.95-6.88 (1H, m), 3.02-2.99 (2H, m), 2.63-2.54 (4H,m) and 2.25-2.16 (2H, m).Preparation 4

Ethyl (diethoxyphosphinyl)acetate (5.16 mL, 26 mmol) was added dropwiseto a slurry of sodium hydride (60% dispersion in mineral oil, 988 mg,24.7 mmol) in tetrahydrofuran (60 mL) and the mixture was stirred atroom temperature for 1 h. The ketone from Preparation 2 (5 g, 13 mmol)in tetrahydrofuran (50 mL) was added dropwise over 20 min. and themixture was stirred at room temperature for 18 h. Water was added andthe mixture was extracted with ethyl acetate. The combined organicfractions were washed with water, dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with isohexane:EtOAc(85:15), to give the product as a white solid (5.2 g, 88%). ¹H NMR (400MHz, CDCl₃) δ 7.41-7.36 (4H, m), 7.18-7.13 (1H, m), 7.11-7.05 (1H, m),6.93-6.86 (1H, m), 5.64 (1H, s), 4.14-4.10 (2H, m), 3.99-3.96 (1H, m),2.91-2.80 (2H, m), 2.42-2.38 (1H, m), 2.31-2.04 (3H, m), 1.89-1.78 (1H,m), 1.28-1.24 (3H, m).Preparation 5

The ketone from Preparation 2, (0.1 g, 0.26 mmol) in methanol (2 ml) wastreated with NaBH₄ (0.098 g, 0.26 mmol) and stirred for 1 hour. Thereaction was quenched with HCl (1N, 10 ml), diluted with ethyl acetate(20 ml), then the organic phase was separated, dried (MgSO₄) andevaporated to dryness. The cis and trans products were purified onsilica eluting with hexane-ethyl acetate mixtures.

(a) (trans) 0.052 g. ¹H NMR CDCl₃ 7.39-7.33 (4H, m), 7.11-7.02 (2H, m),6.88-6.82 (1H, m), 3.80-3.73 (1H, m), 2.80-2.60 (2H, m), 2.22-2.16 (2H,m), 2.08-2.04 (2H, m), 1.53 (1H, br) and 1.27-1.13 (2H, m).

(b) (cis) ¹H NMR (CDCl₃) 7.40 (4H, s), 7.16-7.03 (2H, m), 6.90-6.83 (1H,m), 3.97-3.95 (1H, m), 3.77-3.68 (1H, m), 3.51-3.49 (1H, m), 2.61-2.53(2H, m), 1.91-1.83 (2H, m) and 1.50-1.42 (2H, m).

Preparation 6

The trans cyclohexanol from Preparation 5 (2.7 g, 6.9 mmol) andtriethylamine (1.45 mL, 10.3 mmol) in dichloromethane (50 mL) weretreated with methane sulphonyl chloride (0.645 mL, 8.9 mmol) at −30° C.After 30 mins the mixture was washed with water (20 mL), 10% aqueouscitric acid (20 mL) and saturated aqueous sodium hydrogen carbonate (50mL), dried (MgSO₄) and evaporated to dryness. The solid was trituratedwith ether to give the mesylate (2.6 g) ¹H NMR (CDCl₃) 7.40-7.37 (4H,m), 7.12-7.07 (2H, m), 6.92-6.83 (1H, m), 4.78-4.65 (1H, m), 2.96 (3H,s), 2.88-2.52 (2H, m), 2.29-2.21 (4H, m) and 1.59-1.47 (2H, m).Preparation 7

The trans mesylate from Preparation 6 (103 mg, 0.22 mmol) was dissolvedin toluene (20 ml) and added to a pre-azeotroped sample oftetrabutylammonium cyanide (354 mg, 1.32 mmol). and the mixture waswarmed to 70° C. over 18 hr and then cooled to rt. The solution wasdiluted with water (10 ml) and washed with ethyl acetate (2×50 ml). Theorganic phase was washed with brine (10 ml), dried (MgSO₄) andevaporated. The clear oil obtained was purified by column chromatographyon silica gel eluting with 10-20% ethyl acetate in hexanes, to give thecyanide. ¹H NMR (CDCl₃) 7.42-7.36 (4H, s), 7.10-7.05 (2H, m), 6.89-6.84(1H, m), 2.88-2.86 (1H, m), 2.76-2.72 (2H, m), 2.52-2.45 (1H, m),2.12-2.07 (1H, m) and 1.56-1.49 (1H, m).Preparation 8

The cyanide from Preparation 7 (143 mg, 0.36 mmol) wasdissolved/suspended in a mixture of glacial acetic acid (10 ml) andconc. HCl (6 ml) and heated at 110° C. for 15 hours. The mixture wascooled, diluted with ethyl acetate and washed with water (×3), dried(MgSO₄) and evaporated to dryness. This crude residue (153 mg) waspurified by preparative tlc (5% methanol in dichloromethane/1% aceticacid). ¹H NMR (CDCl₃) 7.38-7.35 (4H, s), 7.08-7.06 (2H, m), 6.90-6.84(1H, m), 2.65-2.58 (2H, m), 2.38-2.33 (3H, m), and 1.75-1.49 (4H, m).Preparation 9

The cyanide from Preparation 8 (50 mg, 0.12 mmol) was dissolved in amixture of tetrahydrofuran (4.5 ml) and water (0.5 ml) and stirred at20° C. The mixture was treated with hydrogen peroxide (20 ml, 0.6 mmol)and then with lithium hydroxide (6 mg, 0.25 mmol) for 2 hours. Hydrogenperoxide (20 ml, 0.6 mmol) and then with lithium hydroxide (6 mg, 0.25mmol) were added and the mixture was stirred at rt. for 72 hrs. Themixture was cooled, diluted with ethyl acetate and washed with water(×2) and sat. sodium bisulphite, dried (MgSO₄) and evaporated todryness. This crude residue (51 mg) was purified by preparative tlc (20%ethyl acetate in hexanes) ¹H NMR (CDCl₃) 7.37 (4H, s), 7.10-7.02 (2H,m), 6.90-6.84 (1H, m), 5.57 (2H, brs), 2.54-2.48 (3H, m), 2.43-2.39 (1H,m), 2.19-2.15 (2H, m) and 1.62-1.50 (3H, m).Preparation 10

To a solution of potassium tert butoxide (1.0M in THF, 3.20 Kg, 3.55mol) in tetrahydrofuran (2.1 L) was added diethyl(cyanomethyl)phosphonate (642 g, 3.62 mol), maintaining the temperaturebelow 5° C. The resulting solution was aged for 2 h and a solution of4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexanone (1.07Kg, 2.78 mol) (Preparation 2) in tetrahydrofuran (3.9 L) was added.After the reaction was completed, isopropyl acetate (13.1 L) and water(26.3 L) were added. The organic layer was washed with brine and thenconcentrated to 1 L. Heptane (10.5 L) was added. The resulting solid wasfiltered, washed with heptane, dried in vacuo at 37° C. and thenslurried in diethyl ether (5 L). Filtration and drying in vacuo afforded989 g (87% yield) of[4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexylidene]acetonitrile.¹H NMR (CDCl₃) 7.41-7.34 (4H, m), 7.25-7.06 (2H, m), 6.94-6.87 (1H, m),5.12 (1H, s), 3.05-3.03 (1H, m), 2.92-2.86 (2H, m), 2.54-2.50 (1H, m),and 2.30-2.03 (4H, m).

Example 1

Sodium borohydride (313 mg, 8.23 mmol) was added to a mixture of theunsaturated ester from Preparation 4 (3.74 g, 8.23 mmol) and nickel (II)chloride (2.67 g, 20.6 mmol) in ethanol (100 mL). The mixture wasstirred at room temperature for 20 min., then water (100 mL) was added.The mixture was filtered through Hyflo™, washing with ethanol and ethylacetate. The solvent was evaporated under reduced pressure and theresidue was partitioned between ethyl acetate and water. The organiclayer was collected, dried (MgSO₄) and the solvent was evaporated underreduced pressure. The residue was purified by flash columnchromatography on silica gel, eluting with isohexane:EtOAc (85:15), togive the faster running cis-isomer, as an oil (1.36 g, 36%), ¹H NMR (400MHz, CDCl₃) δ 7.37-7.30 (4H, m), 7.09-7.00 (2H, m), 6.86-6.79 (1H, m),4.14 (2H, q, J=7.1 Hz), 2.47 (2H, d, J=7.6 Hz), 2.46-2.38 (2H, m),2.19-2.14 (1H, m), 1.76-1.71 (2H, m), 1.57-1.48 (4H, m), 1.27 (3H, t,J7.1 Hz);

and the slower running trans-isomer, as an oil (200 mg, 5.3%). ¹H NMR(400 MHz, CDCl₃) δ 7.39-7.34 (4H, m), 7.10-7.03 (2H, m), 6.88-6.82 (1H,m), 4.08 (2H, q, J=7.1 Hz), 2.98-2.85 (1H, m), 2.67-2.53 (1H, m),2.22-2.11 (2H, m), 2.06 (2H, d, J=6.9 Hz), 2.01-1.85 (3H, m), 1.20 (3H,t, J=7.1 Hz), 1.01-0.90 (2H, m).

Example 2

Lithium hydroxide (350 mg, 14.57 mmol) was added to a solution of thecis-ester from Example 1, (1.33 g, 2.91 mmol) in ethanol (40 mL). Themixture was degassed and stirred at room temperature under nitrogen gasfor 5 h. The mixture was poured into aqueous hydrochloric acid (1 M) andextracted with ethyl acetate. The organic extract was dried (MgSO₄) andthe solvent was evaporated under reduced pressure to give a white solidwhich was then crystallized from IPA to give the product as a whitesolid (950 mg, 76%). ¹H NMR (400 MHz, CD₃OD) δ 7.51-7.49 (2H, m),7.40-7.37 (2H, m), 7.19-7.10 (2H, m), 7.00-6.94 (1H, m), 2.51-2.35 (6H,m), 2.13-2.10 (1H, m), 1.78-1.74 (2H, m), 1.57-1.50 (2H, m).

Example 3

The acid from Example 2 (50 mg, 0.117 mmol), morpholine (30 μL, 0.351mmol), 1-hydroxybenzotriazole (24 mg, 0.176 mmol) and triethylamine (65μL, 0.468 mmol) was stirred in tetrahydrofuran at room temperature undernitrogen gas for 10 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (45 mg, 0.234 mmol) was added to the mixture and stirredfor 24 h. The mixture was poured into aqueous sodium hydroxide (1M) andextracted with ethyl acetate. The organic extract was dried (MgSO₄) andthe solvent was evaporated under reduced pressure. The residue waspurified by flash column chromatography on silica gel, eluting with 5 to10% methanol in dichloromethane, to give the product as a white foam (50mg, 86%). ¹H NMR (400 MHz, CD₃OD) δ 7.50 (2H, d, J=8.6 Hz), 7.37 (2H, d,J=8.6 Hz), 7.19-7.09 (2H, m), 7.00-6.93 (1H, m), 3.69-3.63 (4H, m),3.59-3.56 (4H, m), 2.55 (2H, d, J=7.4 Hz), 2.47-2.39 (4H, m), 2.16-2.07(1H, m), 1.78-1.74 (2H, m), 1.58-1.51 (2H, m). m/z (ES⁺) (M+1) 498+500.

Example 4-15

The following compounds were prepared according to the method of Example3, using the appropriate amine in place of morpholine.

m/z (ES⁺) (M + Ex. —NR₂ Formula M.W. 1) 4

C₂₅H₂₉ClF₂N₂O₃S 510 512 511 513 5

C₃₀H₃₁ClF₂N₂O₃S 572 574 573 575 6

C₂₅H₂₈ClF₂NO₄S 511 513 512 514 7

C₂₇H₂₇ClF₂N₂O₃S 532 534 533 535 8

C₂₆H₂₈ClF₂N₃O₃S 535 537 536 538 9

C₂₈H₃₂ClF₂NO₅S 567 569 568 570 10

C₂₈H₃₂ClF₂NO₅S 567 569 568 570 11

C₂₈H₃₂ClF₂NO₅S 567 569 568 570 12

C₂₈H₃₂ClF₂NO₅S 567 569 568 570 13

C₂₅H₂₈ClF₂NO₃S 495 497 496 498 14

C₂₉H₃₄ClF₂NO₅S 581 583 582 584 15

C₂₉H₃₄ClF₂NO₅S 581 583 582 584

Example 16

Lithium hydroxide (20 mg, 0.833 mmol) was added to a solution of esterfrom Example 9 (95 mg, 0.167 mmol) in ethanol (12 ml) and water (4 ml).The mixture was degassed and stirred at room temperature under nitrogengas for 18 h. The mixture was poured into aqueous hydrochloric acid (1M)and extracted with ethyl acetate. The organic extract was dried (MgSO₄)and the solvent was evaporated under reduced pressure to give theproduct as a white solid (75 mg, 83%). ¹H NMR (400 MHz, CD₃OD) δ 7.50(2H, d, J=8.6 Hz), 7.38 (2H, d, J=8.6 Hz), 7.19-7.10 (2H, m), 7.00-6.93(1H, m), 4.37-4.32 (1H, m), 3.98-3.90 (1H, m), 3.26-3.18 (1H, m),2.90-2.82 (1H, m), 2.64-2.38 (7H, m), 2.10-2.06 (1H, m), 2.00-1.91 (2H,m), 1.78-1.49 (6H, m). m/z (ES⁺) (M+1) 540+542.

Examples 17-21

The following compounds were prepared according to the method of Example16 using the appropriate esters from Examples 10-15.

m/z (ES⁺) Ex. —NR₂ Formula M.W (M + 1) 17

C₂₆H₂₈ClF₂NO₅S 539 541 540 542 18

C₂₈H₃₂ClF₂NO₅S 539 541 540 542 19

C₂₈H₃₂ClF₂NO₅S 539 541 540 542 20

C₂₇H₃₀ClF₂NO₅S 553 555 554 556 21

C₂₇H₃₀ClF₂NO₅S 553 555 554 556

Examples 22-39

These Examples were prepared by the following method, using theappropriate amine free base or amine salt with prior neutralization.

To a stirred suspension ofcis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexaneaceticacid (Example 2, 0.15 g, 0.35 mmol) in dichloromethane (5 ml) was addedoxalyl chloride (0.05 ml, 0.57 mmol) and dimethylformamide (1 drop).After 30 minutes the solution was evaporated to a small volume and to asolution of the residue in dichloromethane (5 ml) was added the desiredamine (1.75 mmol). After stirring the solution for 20 minutes thesolvent was removed in vacuo and the residue purified by chromatographyon silica gel eluting with increasing concentrations of ethyl acetate inisohexane (25%, 50%). The fractions containing the product wereevaporated to give the product amide. Chromatographic purification wasperformed on silica gel using appropriate concentrations of ethylacetate in isohexane, ethyl acetate or methanol in ethyl acetate whereappropriate. MS m/z Example No. R (M + H) m.p. 22 NH-cyclobutyl 482, 484192-193° C. 23 NH₂ 428, 430 187-189° C. 24 NHMe 442, 444 200-201° C. 25NHEt 456, 458 146-147° C. 26 NH^(n)Pr 470, 472 150-151° C. 27 NH^(i)Pr470, 472 124-125° C. 28 NMe₂ 456, 458 29 NHCH₂CH₂Ph 532, 534 30 NHCH₂CF₃510, 512 31

546, 548 32 NHCH₂-cyclopropyl 482, 484 187-188° C. 33 NH-cyclopentyl496, 498 182-183° C. 34 NH-cyclopropyl 468, 470 145-147° C. 35 NH^(n)Bu484, 486 Oil 36 NH^(t)Bu 484, 486 102-110° C. 37 NHCH(Et)₂ 498, 50089-92° C. 38 NH-allyl 468, 470 132-134° C. 39 NHNH^(t)Bu 499, 501

Example 40

Step (1)

To a solution of the acid from Example 2 (1 g) in DCM (50 ml) and ethylacetate (30 ml) was added pentafluorophenol (1.5 equiv.) and DCC (1.5equiv.) and stirred at room temperature for 1 h. The reaction mixturewas evaporated in vacuo, taken up in ethyl acetate and filtered. Thefiltrate was evaporated in vacuo to yield the pentafluorophenol ester ofsufficient purity to use in subsequent reactions without furtherpurification.

Step (2)

To the active ester prepared in Step (1) (200 mg, 0.33 mmol) dissolvedin dry THF (3 ml) and under nitrogen was added hydrazine (1 M solutionin THF, 1.3 ml, 1.32 mmol). After 3 h the reaction was concentrateddiluted with water, extracted with ethyl acetate (×3), washed with,water, brine, dried (MgSO₄), filtered and evaporated. Purified by flashcolumn chromatography (1:1 ^(i)hexane/ethyl acetate to ethyl acetate+3%triethylamine) to give a white solid (50 mg). MS (EI+) 444 (MH+).

Example 41

A solution of the active ester from step (1) of Example 40 in DMF wastreated with acetamidoxime at room temperature. The reaction mixture wasstirred for 0.5 h, diluted with ethyl acetate, washed with water, dried,filtered and evaporated in vacuo. Purification by column chromatographygave the desired product as a white solid (180 mg, 100%). MS MH+485(487).

Example 42

A solution of the oxime from Example 41 (100 mg) in THF (5 ml) wastreated with potassium tert-butoxide solution (3 equiv.) and stirred atroom temperature for 15 mins. The reaction mixture was diluted withwater and ethyl acetate. The organic phase was washed, dried, filteredand evaporated. Purification by column chromatography gave the desiredproduct (65 mg, 62%) as a white solid. MS MH+ 467(469).

Example 43

A solution of the amide from Example 23 (100 mg) was dissolved indioxane and treated with Lawesson's reagent and stirred at roomtemperature overnight. The reaction mixture was filtered and thefiltrate was evaporated in vacuo. Purification by column chromatographygave the thioamide (50 mg, 52%) as a white solid. A solution of theforegoing thioamide (40 mg) in ethanol (2 ml) was treated withchloroacetone (1.3 equiv.) and refluxed for 4 h. The reaction mixturewas evaporated in vacuo. Trituration from hexane-ethyl acetate gave thedesired product (26 mg, 59%) as a white solid. MS MH+ 482(484).

Example 44

A solution of the active ester from Example 40 step (1) in DMF wastreated with acetic hydrazide and stirred at room temperature for 15min. The reaction mixture was diluted with ether and the precipitate wascollected by filtration and washed several times with ether to give theintermediate diacyl hydrazide as a white solid. A solution of theforegoing compound (100 mg) in dioxane was treated with Lawesson'sreagent (2 equiv.) and stirred at room temperature for 1 h. The reactionmixture was evaporated in vacuo. Purification by column chromatographygave the desired product (55 mg, 52%) as a white solid. MS MH+ 483(485).

Example 45

Method (a)

To a solution of the cis amide from Preparation 9 (46 mg) and pyridine(0.053 ml) in tetrahydrofuran (1 ml) was added trifluoroacetic anhydride(0.056 ml). The solution was stirred at room temperature for 2 hourswhen 0.5M−HCl (aqueous) and ethyl acetate were added. The organic phasewas dried (MgSO₄), evaporated to a small volume and purified bychromatography on silica gel, eluting with isohexane:ethyl acetate (5:1)to give the desired product as a colourless solid. ¹H NMR (360 MHz,CDCl₃) Λ 1.61-1.70 (2H, m), 1.86-1.94 (2H, m), 2.03-2.10 (1H, m),2.42-2.45 (4H, m), 2.51 (2H, d J 8.0 Hz), 6.8 (1H, m), 7.02-7.09 (2H,m), 7.30 (2H, d J 8.6 Hz), 7.36 (2H, d J 8.7 Hz).

Method (b)

A solution of[4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexylidene]acetonitrile(Preparation 10) (1005 g, 2.5 mol) in tetrahydrofuran (10.1 L) wascooled to −60° C. and L-Selectride™ (1.0M in tetrahydrofuran, 2.50 Kg,2.81 mol) was added slowly, maintaining the temperature at −60° C. Thesolution was aged for 60 minutes, warmed to −30° C. and treated with 5Msodium hydroxide (285 mL) and aqueous hydrogen peroxide (27%) (960 mL).Then sodium metabisulphite (95 g) was added at −5° C. and the resultingmixture was allowed to warm to 15° C. The solution was transferred intoa mixture of isopropyl acetate (16.7 L), water (15.1 L) and sat. brine(3.7 L). The organic phase was washed with water:sat. brine (1:1, 14 L)and sat. brine (7.3 L). The solution was then concentrated to 1.5 L andheptane (10 L) was added. The resulting solids were filtered and washedwith 5% isopropyl acetate in heptane (4 L), then dried under vacuum at37° C. to affordcis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexaneacetonitrile,(970 g, 95% yield).

Example 46

To a solution of the nitrile from Example 45 (0.43 g) indimethylformamide (0.5 ml) was added ammonium chloride (0.15 g) andsodium azide (0.15 g) and the mixture was heated at 100° C. for 12 h.0.2M−HCl (5 ml) and ethyl acetate (5 ml) were added and the organicphase was washed with water (5 times) and dried (MgSO₄). The solvent wasremoved in vacuo and the residue was purified by chromatography onsilica gel (eluting with ethyl acetate, 5% methanol in ethyl acetate) togive the desired product MS m/z 451 (M−H)

Example 47

The nitrile from Example 45 (300 mg) was dissolved in methanol (3 ml)and ether (20 ml), cooled to 0° C. and treated with HCl gas for 10minutes. The reaction vessel was stoppered and left to stand at roomtemperature overnight. The reaction mixture was evaporated in vacuo togive the imidate ether hydrochloride salt (350 mg, ca 100%) as a whitesolid.

A solution of the foregoing imidate ether hydrochloride salt (100 mg) inmethanol (10 ml) was treated with acetic hydrazide (1.5 equiv.) andstirred at room temperature for 5 min. The reaction mixture wasevaporated in vacuo and taken up in Dowtherm A, treated with ammoniumchloride (100 mg) and heated at 190° C. for 2 h. The reaction mixturewas cooled and purified by column chromatography to give the desiredproduct (24 mg, 24%) as a white solid. MS MH+ 467(469).

Example 48

A suspension of the hydrazide of Example 40 (160 mg) in methanol (10 ml)was treated with a solution of acetamidine (2 equiv.) in ethanol (1 ml)and stirred at room temperature overnight, then refluxed for 2 h. Thereaction mixture was evaporated in vacuo, dissolved inN-methyl-pyrrolidinone (2 ml) and xylene (30 ml) and refluxed overnightwith the azeotropic removal of water. The reaction mixture wasevaporated in vacuo, dissolved in ethyl acetate and washed with water(three times). The organic phase was dried, filtered and evaporated.Purification by column chromatography gave the desired product (137 mg,76%) as a white solid. MS MH+466(468).

Example 49

A solution of the triazole from Example 48 (50 mg) in DMF (1 ml) wastreated with sodium hydride (1.1 equiv.) and, after 5 minutes, methyliodide (1.5 equiv.). After 1 h, the reaction mixture was diluted withethyl acetate and water. The organic layer was washed with water, dried,filtered and evaporated in vacuo. Purification by column chromatographygave the desired product (33 mg, 64%) as a white foam. ¹H NMR indicatedthis compound to be a mixture of N1/N2 methylated regioisomers. MS MH+480(482).

Example 50

A solution of the active ester from Example 40 step (1) (200 mg) intoluene was treated with a suspension of semicarbazide hydrochloride(1.1 equiv.) in DMF and triethylamine (2.2 equiv.) and stirred at roomtemperature for half an hour. The reaction mixture was diluted withether and filtered. The residue was washed with ether to give the crudeacyl semicarbazide as a white solid.

A suspension of this material (150 mg) in 1 M NaOH solution (20 ml) anda small amount of 1,4-dioxane was refluxed overnight. The reactionmixture was cooled and acidified with 1 M HCl. The resulting precipitatewas collected by filtration, washed with water and ether several timesand dried in vacuo to give the desired product as a white solid. MS MH+468(470).

Example 51

The hydrazide prepared in Example 40 (40 mg, 0.09 mmol) was dissolved intriethyl orthoformate (3 ml) and heated at 150° C. for 18 h. Reactionwas concentrated and purified by flash chromatography (1:1^(i)hexane/ethyl acetate) to give a colourless glassy solid (12 mg). ¹HNMR (CDCl₃) 1.55-1.62 (2H, m), 1.77-1.82 (2H, m), 2.20-2.28 (1H, m),2.44 (1H, s), 2.50 (3H, dd, J=5.5, 14.5 Hz), 3.07 (2H, d, J=7.8 Hz),6.80-6.87 (1H, m), 7.01-7.09 (2H, m), 7.31-7.38 (4H, m), 8.36 (1H, s).

Example 52

To the acid prepared in Example 2 (1.0 g, 2.3 mmol) dissolved in THF (80ml) under nitrogen and cooled to 0° C. were added triethylamine (0.4 ml,2.8 mmol) and isobutylchloroformate (0.36 ml, 2.8 mmol). Reaction wasstirred at 0° C. for 2 h and then the solid in the reaction mixture wasremoved by filtration. The filtrate was recooled to 0° C. and sodiumborohydride (435 mg) in water (10 ml) added dropwise and the reactionwas stirred for 1 h. Reaction was concentrated, diluted with ethylacetate, washed with water, brine, dried (MgSO₄), filtered andevaporated. Purified by flash chromatography (1:1 ^(i)hexane/ethylacetate) to give the alcohol (0.96 g).

To the alcohol (400 mg, 0.97 mmol) dissolved in DCM (20 ml) was addedDess-Martin periodinane (453 mg, 1.1 mmol). Reaction stirred for 1 h andthen filtered through a pad of Celite™ and the filtrate evaporated andthe residue purified by flash chromatography (2:1 ^(i)hexane/ethylacetate) to give the aldehyde (250 mg) which was dissolved in ethanol (5ml), cooled to 0° C. and treated with glyoxal (40% w/w aq solution, 0.2ml) and ammonia (25% w/w aq. solution, 1 ml). After 30 min the reactionwas allowed to warm to room temperature and stirred for 15 h. Afterconcentration the residue was diluted with brine and extracted withethyl acetate (×3). Organic extracts were dried (MgSO₄), filtered andevaporated to give the imidazole as a white solid (150 mg). ¹H NMR(CDCl₃) 1.45-1.55 (2H, m), 1.70-1.75 (2H, m), 2.17-2.22 (1H, m), 2.46(4H, dd, J=5.6, 14.0 Hz), 2.88 (2H, d, J=7.7 Hz), 6.78-6.85 (1H, m),6.98 (2H, s), 7.00-7.05 (2H, m), 7.31-7.36 (4H, M), 9.1-9.8 (1H, br).

Example 53

The imidazole prepared in Example 52 (35 mg, 0.078 mmol) was dissolvedin dry DMF (2 ml) and treated with potassium carbonate (53 mg, 0.39mmol) and iodomethane (6 μl, 0.096 mmol) and allowed to stir for 48 h.The reaction was diluted with water and extracted with ethyl acetate(×3). Organic extracts were dried (MgSO₄), filtered and evaporated andpurified by flash chromatography (ethyl acetate) to give a white solid(8 mg). ¹H NMR (CDCl₃) 1.51-1.59 (1H, m), 1.80 (4H, dd, J=3.9, 10.5 Hz),2.19-2.26 (1H, m), 2.42-2.57 (3H, m), 2.80 (2H, d, J=7.7 Hz), 3.60 (3H,s), 6.79 (1H, d, J=1.1 Hz), 6.81-6.86 (1H, m), 6.94 (1H, d, J=1.4 Hz),7.00-7.08 (2H, m), 7.34 (4H, d, J=4.2 Hz).

Example 54

The acid from Preparation 8 (153 mg) was dissolved in dry THF (10 ml)and cooled to 0° C. under nitrogen. Triethylamine (61 μL, 0.43 mmol) andisobutylchloroformate (57 μL, 0.43 mmol) were added and the mixturestirred at 0° C. for one hour. The precipitate that had formed wasremoved by filtration and washed with a further 5 ml of dry THF. Thecombined THF layers were recooled to 0° C. and sodium borohydride (70mg, 1.84 mmol) as a solution in water (2 ml) was added witheffervescence. After stirring for 30 minutes at 0° C., the reaction wasdiluted with ethyl acetate, washed with ammonium chloride solution,sodium bicarbonate solution and brine then dried (MgSO₄) and evaporatedto dryness. The residue was purified by column chromatography elutingwith ethyl acetate:hexane (1:3) to afford the desired alcohol (75 mg).¹H NMR (CDCl₃) 7.39-7.31 (4H, m), 7.10-7.01 (2H, m), 6.88-6.81 (1H, m),3.71 (2H, d, J=7.5 Hz), 2.46-2.32 (4H, m), 1.90-1.85 (2H, m), 1.78-1.74(1H, m) and 1.54-1.44 (2H, m). m/z=423 [MNa]⁺

Example 55

A stirred solution of the alcohol from Example 54 (294 mg, 0.74 mmol) inDCM (10 ml) was cooled to −30° C. Triethylamine (15511, 1.11 mmol) thenmethanesulfonyl chloride (68 μl, 0.89 mmol) were added and the mixturestirred for 30 minutes at −30° C. The reaction was diluted with water,warmed to ambient temperature and extracted with DCM. The organic layerwas washed with citric acid solution and sodium bicarbonate solution,dried (MgSO₄) and evaporated to dryness. The residue (321 mg) could beused without further purification or purified by column chromatographyeluting with ethyl acetate:hexane (1:3) to remove small quantities ofthe trans isomer to afford the desired product. (272 mg). ¹H NMR (CDCl₃)7.36 (2H, d, J=8.5 Hz), 7.31 (2H, d, J=8.5 Hz), 7.08-7.02 (2H, m),6.87-6.83 (1H, m), 4.29 (1H, d, J=7.5 Hz), 3.05 (3H, s), 2.46-2.42 (4H,m), 2.05-2.02 (1H, m), 1.93-1.88 (2H, m) and 1.62-1.55 (2H, m). m/z=501[MNa]⁺

Example 56

To a stirred solution of the alcohol from Example 54 (59 mg, 0.15 mmol)in dry THF (5 ml) cooled to 0° C. under nitrogen was addedchlorosulfonyl isocyanate (18 μl, 0.21 mmol). The mixture was stirredfor 45 minutes at this temperature then sodium metabisulfite (84 mg,0.44 mmol) as a solution in water (1 ml) was added and stirringcontinued for 16 hours at room temperature. Ethyl acetate was added andthe mixture washed with water (×2), brine, dried (MgSO₄) and evaporatedto leave a residual solid (73 mg) which was triturated with ether andfiltered to afford the desired product (35 mg). ¹H NMR (DMSO) 7.61 (2H,d, J=8.5 Hz), 7.36 (2H, d, J=8.5 Hz), 7.35-7.30 (1H, m), 7.25-7.10 (2H,m), 6.47 (2H, br s), 3.95 (2H, d, J=7.5 Hz), 3.16 (1H, m), 2.44 (1H, m),2.23-2.14 (2H, m), 1.85-1.67 (3H, m) and 1.38-1.26 (2H, m). m/z=444[MH]⁺

Example 57

A stirred solution of 1,2,4-triazole sodium derivative (95 mg, 1.04mmol) in DMSO (5 ml) and the mesylate from Example 55 (100 mg, 0.21mmol) were heated to 100° C. for 17 hours. The reaction was cooled,diluted with dichloromethane and washed with water, brine (×2), dried(MgSO₄) and evaporated to leave a residue which was purified bypreparative thin layer chromatography eluting with ether:dichloromethane1:1 to afford the desired product. ¹H NMR (CDCl₃) 8.09 (1H, s), 7.95(1H, s), 7.36 (2H, d, J=8.5 Hz), 7.31 (2H, d, J=8.5 Hz), 7.07-7.02 (2H,m), 6.85-6.81 (1H, m), 4.27 (2H, d, J=8 Hz), 2.58-2.39 (4H, m),2.28-2.22 (1H, m), 1.75-1.68 (2H, m) and 1.6-1.48 (2H, m). m/z=452[MH]⁺.

Example 58

To a stirred solution of the alcohol from Example 54 (114 mg, 0.29 mmol)in dry THF (10 ml) was added 3-hydroxypyridine (30 mg, 0.32 mmol),triphenylphosphine (164 mg, 0.63 mmol) and diethylazodicarboxylate(5511, 0.35 mmol) and the resulting solution stirred at ambienttemperature for 20 hours. The mixture was evaporated and purified bycolumn chromatography eluting with ethyl acetate:hexane (1:1) to affordthe desired product. (52 mg). ¹H NMR (CDCl₃) 8.33 (1H, s), 8.24 (1H, s),7.37-7.30 (4H, m), 7.25-7.20 (2H, m), 7.11-7.03 (2H, m), 6.88-6.82 (1H,m), 4.07 (2H, d, J=7.5 Hz), 2.50-2.43 (4H, m), 2.13-2.09 (1H, m),2.01-1.96 (2H, m) and 1.67-1.56 (2H, m). m/z=478[MH]⁺

Example 59

Morpholine (91 μL, 1.04 mmol) was added to a solution of thecis-mesylate from Example 55 (50 mg, 0.104 mmol) in acetonitrile (2 mL)and the mixture was stirred at 80° C. for 3 days. The mixture was cooledand the solvent was evaporated under reduced pressure and the residuewas dissolved in ethyl acetate. The mixture was washed with aqueoussodium hydroxide (1M), dried (MgSO₄) and the solvent was evaporatedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel, eluting with isohexane:EtOAc (1:1), togive the product as a white foam (30 mg, 61%). ¹H NMR (360 MHz, CD₃OD) δ7.51-7.48 (2H, m), 7.44-7.38 (2H, m), 7.19-7.09 (2H, m), 7.00-6.93 (1H,m), 3.70-3.67 (4H, m), 2.56-2.24 (10H, m), 1.85-1.81 (3H, m), 1.50-1.42(2H, m).

Example 60

To a stirred solution of pyrrolidin-2-one (23 mg, 0.27 mmol) in DMF (10ml) under nitrogen was added sodium hydride (11 mg of a 60% dispersionin mineral oil, 0.27 mmol) and the mixture stirred at ambienttemperature for 20 minutes. After this time, a solution of the mesylatefrom Example 55 (44 mg, 0.09 mmol) in DMF (2 ml) was added and themixture heated to 80° C. for 4 hours. The reaction was cooled, dilutedwith ethyl acetate and washed with ammonium chloride solution, sodiumbicarbonate solution, brine, dried (MgSO₄) and evaporated to leave aresidue which was purified by preparative thin layer chromatographyeluting with ethyl acetate:hexanes 3:1 to afford the desired product (9mg). ¹H NMR (CDCl₃) 7.37 (4H, s), 7.08-7.00 (2H, m), 6.88-6.81 (1H, m),3.38-3.34 (4H, m), 2.51-2.38 (6H, m), 2.06-1.98 (2H, m), 1.92-1.87 (1H,m), 1.70-1.64 (2H, m) and 1.51-1.42 (2H, m). m/z=292 [M-ArSO₂ ⁻]⁺

Using the general procedure of Example 60, and substituting theappropriate nucleophile for pyrrolidin-2-one, the following wereprepared:

Example No. NR₂ m/z 61

294 [M-ArSO₂ ⁻]⁺ 62

292 [M-ArSO₂ ⁻]⁺ 63

275 [M-ArSO₂ ⁻]⁺451 [MH]⁺ 64

302 [M-ArSO₂ ⁻]⁺478 [MH]⁺ 65

321 [M-ArSO₂ ⁻]⁺497 [MH]⁺ 66

307 [M-ArSO₂ ⁻]⁺483 [MH]⁺ 67

*** 68*

452 [MH]⁺ 69*

452 [MH]⁺ 70

451 [MH]⁺ 71**

453 [MH]⁺ 72**

453 [MH]⁺ 73

482 [MH]⁺*obtained as a mixture using 1,2,3-triazole as nucleophile, andseparated by preparative TLC (2:1 DCM/hexane 2% MeOH).**obtained as a mixture using 1,2,3,4-tetrazole as nucleophile, andseparated by preparative TLC.*** ¹H NMR (CDCl₃) 7.36 (4 H, br s), 7.06-7.04 (2 H, m), 6.89-6.80 (1 H,m), 3.64-3.62 (2 H, d, J = 7.5 Hz), 2.53-2.46 (4 H, m), 2.04-2.01 (1 H,m), 1.69-1.68 (2 H, m) and 1.51-1.50 (2 H, m).

Example 74

A stirred solution of 2-hydroxypyridine (60 mg, 0.63 mmol) in DME (4 ml)and DMF (1 ml) under nitrogen was cooled to 0° C. Sodium hydride (28 mgof a 60% dispersion in mineral oil, 1.15 mmol) was then added and thesuspension stirred at 0° C. LiBr (109 mg, 1.26 mmol) was added 10minutes later. After this time, the mixture was warmed to ambienttemperature and stirred for 15 minutes. A solution of the mesylate fromExample 55 (60 mg, 0.13 mmol) in DMF (2 ml) was added and the mixtureheated to 65° C. for 18 hours. The reaction was cooled, diluted withethyl acetate and washed with ammonium chloride solution, sodiumbicarbonate solution and brine then dried (MgSO₄) and evaporated toleave a residue which was purified by preparative thin layerchromatography eluting with EtOAc:Hexane 1:5 to afford the desiredproduct (4 mg).

¹H NMR (CDCl₃) 7.55-7.30 (5H, m), 7.25-7.22 (1H, dd J=7.0, 2.0 Hz),7.09-7.00 (2H, m), 6.85-6.78 (1H, m), 6.58-6.55 (1H, d, J=9.0 Hz),6.18-6.14 (1H, m), 4.02-3.99 (2H, d, J=8.0 Hz), 2.62-2.55 (2H, m), 2.44(2H, m), 2.19-2.17 (1H, m), 1.80-1.76 (2H, m) and 1.6-1.5 (2H, m).

Example 75

To a stirred solution of the mesylate from Example 55 (90 mg, 0.19 mmol)in DMF (10 ml) under nitrogen was added sodium azide (49 mg, 0.76 mmol)and the mixture stirred and heated to 100° C. for 2 hours. After thistime, the reaction was cooled, diluted with water and extracted withethyl acetate (×2), the combined organic layers were washed with water,dried (MgSO₄) and evaporated to leave a residue (76 mg) which waspurified by preparative thin layer chromatography eluting with 4%EtOAc:Hexane to afford the desired product.

¹H NMR (CDCl₃) 7.38-7.30 (4H, m), 7.09-7.01 (2H, m), 6.87-6.80 (1H, m),3.43-3.41 (2H, d, J=8.0 Hz), 2.46-2.35 (4H, m), 1.87-1.79 (3H, m),1.56-1.50 (2H, m).

Example 76

Step (1)

The alcohol from Example 54 (181 mg, 0.46 mmol) was dissolved in THF andpyridine (37 μl, 0.46 mmol) added followed by 4-nitrophenylchloroformate (103 mg, 0.51 mmol). The reaction was stirred overnight atroom temperature then the solvent removed in vacuo and the reactiontaken up in ether and washed with water (×2) and brine (×2), dried(MgSO₄) and evaporated to a foam (247 mg). Product was purified by flashcolumn chromatography (1% MeOH, 99% DCM) to yield the desired4-nitrophenylcarbonate (230 mg)

Step (2)

The carbonate (74 mg, 0.14 mmol) was dissolved in DMF (2 ml) andisopropylamine (23 μl, 0.28 mmol) added. The reaction was stirred for 10minutes then diluted with ethyl acetate and washed with 2N NaOH (×3) andbrine (×3), dried (MgSO₄) and evaporated to dryness. The crude productwas purified by prep plate (2:1 hexane:ethyl acetate) affording thedesired product (18 mg). ¹H NMR (CDCl₃) 7.38-7.30 (4H, m), 7.09-6.99(2H, m), 6.88-6.79 (1H, m) 4.57-4.48 (1H, s, broad), 4.13 (2H, d, J=8.5Hz), 3.88-3.71 (1H, m), 2.49-2.38 (4H, m), 1.92-1.80 (3H, m) 1.55-1.41(2H, m), and 1.16 (6H, d, J=6.5 Hz).

Example 77

The carbonate from Example 76 step (1) (56 mg, 0.14 mmol) was dissolvedin THF (2 ml) and ethylamine (0.4 ml, 0.28 mmol, 2M solution in THF)added. The reaction was stirred for 10 minutes then evaporated to afoam. The reaction was taken up in ethyl acetate and washed with 2N NaOH(×3) and brine (×3), dried (MgSO₄) and evaporated to dryness. The crudeproduct was purified by prep plate (2:1 hexane:ethyl acetate) affordingthe desired product (18 mg). ¹H NMR (CDCl₃) 7.38-7.30 (4H, m), 7.09-6.99(2H, m), 6.88-6.79 (1H, m) 4.61-4.70 (1H, s, broad), 4.14 (2H, d, J=7Hz), 3.28-3.15 (2H, m), 2.49-2.38 (4H, m), 1.90-1.79 (3H, m) 1.55-1.42(2H, m) and 1.15 (3H, t, J=7 Hz).

Example 78

Prepared as for Example 77 using dimethylamine (2M solution in THF) asstarting material. Yield 7 mg. ¹H NMR (CDCl₃) 7.38-7.30 (4H, m),7.09-6.99 (2H, m), 6.88-6.78 (1H, m), 4.15 (2H, d, J=7 Hz), 2.91 (6H,s), 2.49-2.38 (4H, m), 1.95-1.80 (3H, m) and 1.55-1.48 (2H, m).

Example 79

Prepared as for Example 77 using cyclopropylmethylamine as startingmaterial. Yield 11 mg. ¹H NMR (CDCl₃) 7.38-7.30 (4H, m), 7.09-7.00 (2H,m), 6.88-6.78 (1H, m), 4.87-4.75 (1H, s, broad), 4.14 (2H, d, J=7 Hz),3.08-2.97 (2H, m), 2.47-2.38 (4H, m), 1.98-1.79 (3H, m), 1.55-1.41 (2H,m), 1.0-0.88 (1H, m), 0.53-0.46 (2H, m) and 0.20-0.12 (2H, m).

Example 80

Prepared as for Example 77 using methylamine (8M solution in EtOH) asstarting material. Yield 7 mg. ¹H NMR (CDCl₃) 7.38-7.30 (4H, m),7.09-7.00 (2H, m), 6.88-6.78 (1H, m), 4.68-4.56 (1H, s, broad), 4.14(2H, d, J=7 Hz), 2.81 (3H, d, J=4.89), 2.48-2.38 (4H, m), 1.91-1.76 (3H,m) and 1.56-1.41 (2H, m).

Example 81

To the pentafluorophenol ester prepared in Example 40 step (1) (140 mg,0.23 mmol) dissolved in DCM (3 ml) and under nitrogen were addedmethoxyamine hydrochloride (80 mg, 0.92 mmol) and triethylamine (0.1ml). After 1 h the reaction was concentrated, diluted with ethylacetate, washed with aq. sodium carbonate, water, brine, dried (MgSO₄),filtered and evaporated. Purified by flash column chromatography (1:1^(i)hexane/ethyl acetate to ethyl acetate/methanol) to give a whitesolid (50 mg). ¹H NMR (CDCl₃) 1.56 (2H, br), 1.76 (2H, br), 2.25 (4H,br), 2.44 (4H, br), 3.78 (3H, s), 6.78-6.86 (1H, m), 7.01-7.06 (2H, m),7.29-7.37 (4H, m).

Example 82

To a stirred suspension ofcis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexaneaceticacid (Example 2, 0.224 g, 0.52 mmol) in dichloromethane (5 ml) was addedoxalyl chloride (0.075 ml, 0.86 mmol) and dimethylformamide (1 drop).After 30 minutes the solution was evaporated to a small volume and to asolution of the residue in dichloromethane (5 ml) was addedN,O-dimethylhydroxylamine hydrochloride (0.068 g, 0.58 mmol) anddiisopropylethylamine (0.2 ml, 1.14 mmol). After stirring the solutionfor 30 minutes the solvent was removed in vacuo and the residue purifiedby chromatography on silica gel eluting with increasing concentrationsof ethyl acetate in isohexane (33%, 50%). The fractions containing theproduct were evaporated to give the desired product as a foam. ¹H NMR(360 MHz, CDCl₃) Λ 1.50-1.56 (2H, m), 1.72-1.77 (2H, m), 2.24 (1H, m),2.44 (4H, m), 2.57 (2H, d J 7.3 Hz), 3.2 (3H, s), 3.7 (3H, s), 6.80-6.88(1H, m), 7.01-7.08 (2H, m), 7.31 (2H, dd J 6.7 Hz and 2.3 Hz), 7.36 (2H,dd J 6.7 Hz and 2.3 Hz).

Example 83

To the pentafluorophenol ester prepared in Example 40 step (1) (155 mg,0.25 mmol) dissolved in DMF (3 ml) and under nitrogen were added glycinemethyl ester hydrochloride (125 mg, 1.0 mmol) and triethylamine (0.15ml). After 2 h the reaction was diluted with water, extracted with ethylacetate (×3), washed with, water, brine, dried (MgSO₄), filtered andevaporated. Purified by flash column chromatography (1:1^(i)hexane/ethyl acetate to 9:1 ethyl acetate/methanol) to give a whitesolid (55 mg). ¹H NMR (CDCl₃) 1.08-1.16 (1H, m), 1.30-1.37 (1H, m),1.67-1.71 (1H, m), 1.75-1.79 (2H, m), 1.91-1.95 (1H, m), 2.20-2.26 (1H,m), 2.41 (4H, d, J=7.8 Hz), 3.77 (3H, s), 4.05 (2H, d, J=5.1 Hz), 6.19(1H, br), 6.79-6.85 (1H, m), 7.00-7.07 (2H, m), 7.30-7.37 (4H, m).

Example 84

The glycine ester prepared in Example 83 (50 mg, 0.1 mmol) in a sealedtube and dissolved in a 2M ammonia in methanol solution (3 ml) washeated to 50° C. for 3 h. After cooling to room temperature the reactionmixture was concentrated and purified by trituration with ether to givea white solid (28 mg). MS (EI+): 485 (MH+)

Example 85

The alcohol from Example 54 (4 g, 10 mmol) was dissolved indichloromethane (280 ml) and was treated with Dess Martin periodinane(4.66 g, 11 mmol) and the mixture was stirred for 45 mins before addingsaturated aqueous sodium bisulphite (100 ml) and after 5 mins themixture was separated and the organic phase as washed with saturatedaqueous sodium bicarbonate (100 ml) dried (MgSO₄) and evaporated todryness. The crude residue (4 g) was dissolved in dry dichloromethane(100 ml) and treated with methyl triphenylphosphinoacetate (4.7 g 14mmol), stirring at rt. for 16 hrs. The solvent was evaporated and theresidue was purified by column chromatography on silica gel eluting with10-20% ethyl acetate in hexanes, to give the product. ¹H NMR (CDCl₃)7.37-7.36 (4H, m), 7.10-7.02 (3H, m), 6.87-6.83 (1H, m), 5.91 (1H, d,J=16 Hz), 3.77 (3H, s), 2.55-2.45 (3H, m), 2.40-2.38 (2H, m), 1.95-1.90(2H, m) and 1.65-1.52 (2H, m).

Example 86

The alkene from Example 85 (3.6 g, 9 mmol) was dissolved in ethylacetate (350 ml). The flask was degassed and then 10% palladium oncarbon (400 mg) was added and the mixture stirred under an atmosphere ofhydrogen for 45 mins. The solution was filtered through Celite™ andevaporated. The clear oil obtained was purified by preparative tlceluting with 5% ethyl acetate in hexanes. The oil obtained was thenfurther purified by column chromatography on silica gel eluting with5-10% ethyl acetate in hexane to give the product. ¹H NMR (CDCl₃)7.37-7.34 (4H, m), 7.08-7.00 (2H, m), 6.85-6.81 (1H, m), 3.67 (3H, s),2.45-2.39 (4H, m), 2.33 (2H, t, J=8.4 Hz), 1.81 (2H, q, J=8.4 Hz),1.72-1.68 (2H, m) and 1.60-1.43 (3H, m).

Example 87

A solution ofcis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexaneacetonitrile(Example 45) (967.3 g, 2.36 mol) in toluene (15.8 L) and dichloromethane(4.85 L) was cooled to −63° C. and diisobutyl aluminium hydride (1.0M intoluene, 2.48 Kg, 2.89 mol) was added over 60 minutes. Stirring wascontinued at −60° C. for a further 30 minutes before the solution wastransferred into 0.75M citric acid (25 L). The bi-phasic mixture wasstirred overnight at 20° C., the layers were separated and the organiclayer was washed with 2M hydrochloric acid (15.8 L), 10% sodiumbicarbonate (15.8 L) and water (15.8 L). After evaporation of thesolvents, the residue was crystallised from EtOAc/heptane to affordcis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexaneacetaldehyde(922 g; 95% yield). ¹H NMR (CD₂Cl₂) 9.65 (1H, t, J=1.7 Hz), 7.32-7.20(4H, m), 6.98-6.88 (2H, m), 6.85-6.72 (1H, m), 2.57-2.45 (2H, m),2.45-2.10 (5H, m) and 1.68-1.35 (4H, m).

Example 88

Sodium borohydride (97.9 g, 2.59 mol) was added to a solution ofcis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)-cyclohexaneacetaldehyde(922 g, 2.24 mol) (Example 87) in absolute ethanol (6.3 L) and toluene(500 mL). The reaction was stirred at 4° C. for 60 minutes beforehydrochloric acid (2M, 2.43 L) was added. The mixture was allowed towarm to 20° C. and stirred until a clear solution was obtained. Thelatter was transferred into tert-butyl methyl ether (15.8 L) and water(15.8 L), the layers were separated and the organic layer was washedwith water (15.8 L). The solution was evaporated to dryness, and 2.4 Ltoluene was added to the residue. After the product crystallized,n-heptane (480 mL) was added. The slurry was filtered and washed withcold heptane (1 L). The solid was dried under vacuum at 38° C. toprovidecis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexaneethanol(650 g). Another 144 g was obtained via chromatography of the motherliquors on silica gel, eluting with 30% ethyl acetate in hexanes(combined yield 85%). ¹H NMR CDCl₃ 7.37-7.30 (4H, m), 7.10-7.00 (2H, m),6.86-6.79 (1H, m), 3.73-3.68 (2H, m), 2.42-2.36 (4H, m), 1.78-1.69 (5H,m) and 1.53-1.43 (2H, m).

Example 89

A solution ofcis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexaneethanol(Example 88) (790 g, 1.9 mol) in dichloromethane (7.9 L) was cooled to−25° C. and triethylamine (344 ml, 2.47 mol) was added followed bymethanesulfonyl chloride (154 ml, 1.99 mol) whilst maintaining thetemperature below −25° C. The reaction mixture was aged for 90 min. andthen quenched into water (7.9 L). The layers of the resulting 2-phasemixture were separated. The organic layer was washed with brine (4 L),the brine layer extracted with dichloromethane (2 L), the combinedorganic layers dried over sodium sulfate, and then concentrated todryness. The residue was dissolved in dimethyl sulphoxide (7.9 L), andpotassium cyanide (161 g, 2.47 mol) was added. The solution was stirredat ambient temperature for 16 hours, warmed to 30° C. for 3 hours, andthen transferred into a mixture of isopropyl acetate (8 L) and water (16L). Further isopropyl acetate (30 L) and water (30 L) were added. Thelayers were separated, and the combined organic layers were washed withwater (8 L). The organic layer was concentrated to dryness, and theproduct purified by chromatography on silica gel, eluting withdichloromethane, to givecis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexanepropionitrile(697 g, 87%). ¹H NMR CDCl₃ 7.37-7.29 (4H, m), 7.09-7.00 (2H, m),6.86-6.79 (1H, m), 2.47-2.37 (6H, m), 1.86-1.81 (2H, m), 1.78-1.72 (3H,m) and 1.61-1.52 (2H, m).

Example 90

To a cooled (−80° C.) solution of1-(trimethylsilylethyloxymethyl)-triazole (0.109 g, 0.55 mmol) intetrahydrofuran (2 ml) was added a solution of n-butyl lithium (2.5M inhexanes, 0.22 ml). The solution was stirred at −80° C. for 15 minutes,warmed to 0° C. for 5 minutes and then recooled to −80° C. To the cooledsolution was added a solution ofcis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexaneaceticacid N,O-dimethylhydroxamate (Example 82) (217 mg, 0.46 mmol) intetrahydrofuran (3 ml). After stirring the mixture at −80° C. for 15minutes a saturated solution of aqueous ammonium chloride was added andthe product extracted with ethyl acetate. The organic phase was dried(MgSO₄), evaporated to dryness and purified by chromatography on silicagel (eluting with 25% ethyl acetate in hexane) to give the desiredproduct as a crystalline solid. MS m/z 610,612 (M+H)

Example 91

The triazole from Example 90 (0.117 g) was heated in a mixture ofethanol (10 ml) and 6M−HCl (aqueous) (5 ml) and concentrated HCl (2 ml)for 2 hours at 60° C. Water and ethyl acetate were added and the organicphase was dried (MgSO₄), evaporated in vacuo and the residue purified bychromatography on silica gel (eluting with 50% ethyl acetate in hexane,100% ethyl acetate) to give the desired product as a solid which waswashed with hexane mp 147-154° C. MS m/z 480,482 (M+H). ¹H NMR (360 MHz,CD₄OD) 1.51-1.60 (2H, m), 1.76 (2H, dd, J=14.3 Hz and 3.1 Hz), 2.37 (1H,m), 2.5 (4H m), 3.26 (2H, d, J=7.3 Hz), 6.96 (1H, m), 7.16 (2H, m), 7.40(2H, dt, J=8.7 Hz and 2.23 Hz), 7.51 (2H, dt, J=8.7 Hz and 2.23 Hz),8.51 (1H, s).

Example 92

To a solution of the product of Example 91, (50 mg) in methanol (2 ml)was added sodium borohydride (4.5 mg 0.11 mmol). After 30 minutes ethylacetate and water were added followed by addition of solid citric acid(50 mg). The organic phase was dried (MgSO₄), evaporated to dryness andthe residue chromatographed on silica gel (eluting with ethyl acetatethen 5% methanol in ethyl acetate) to give the desired product as acolourless solid after washing the residue with hexane. MS m/z 482,484(M+H)). ¹H NMR (360 MHz, CD₃OD) 1.43-1.54 (2H, m), 1.75-1.88 (3H, m),1.54-2.0 (1H, m), 2.01-2.16 (1H, m), 2.35-2.55 (5H, m), 6.93-7.00 (1H,m), 7.09-7.18 (2H, m), 7.37 (2H, d, J=8.6 Hz), 7.48 (2H, d, J=8.6 Hz),8.1 (1H, v.broad s).

Example 93

The cis-ester from Example 1 (669 mg, 1.467 mmol) in tetrahydrofuran (14ml) was cooled to −78° C., treated with sodium bis(trimethylsilyl)amide(2.20 ml, 1 M solution in tetrahydrofuran, 2.20 mmol) and stirred whilewarming to room temperature over 2 hours. Methyl iodide (457 μl, 7.36mmol) was then added to the mixture at −20° C. and stirring continued,again warming to room temperature, for 2 hours. The reaction wasquenched with glacial acetic acid (132 μl, 2.20 mmol), diluted withammonium chloride (50% aq., 80 ml) and extracted with ethyl acetate(3×100 ml). Combined organics were then washed with brine (sat., 200ml), dried (MgSO₄) and evaporated in vacuo to give crude (670 mg). Thismaterial was chromatographed on silica, eluting with 8% ethyl acetate inhexanes to give product (272 mg, 40%). ¹H NMR (400 MHz, CDCl₃), 1.16(3H, d, J=6.9 Hz), 1.28 (3H, t, J=7.1 Hz), 1.45-1.51 (2H, m), 1.71-1.77(2H, m), 1.89-1.94 (1H, m), 2.28-2.48 (3H, br), 2.54-2.60 (1H, br),2.70-2.74 (1H, m), 4.09-4.18 (2H, m), 6.77-6.84 (1H, m), 6.99-7.08 (2H,m), 7.26-7.36 (4H, m).

Example 94

A solution of α-methyl ethyl ester from Example 93 (13 mg, 0.028 mmol)in methanol/water/tetrahydrofuran (3:1:1, 1 ml) was degassed and treatedwith lithium hydroxide (3.3 mg, 0.138 mmol) and the mixture heated to90° C. After 1 hour at this temperature, the reaction was cooled to roomtemperature, acidified with hydrochloric acid (1 N, 2 ml), diluted withwater (5 ml) and extracted with ethyl acetate (3×10 ml). Combinedorganics were washed with brine (sat., 30 ml), dried (MgSO₄) andevaporated in vacuo to give crude. This material was purified bypreparative t.l.c., eluting with 3% methanol, 1% acetic acid indichloromethane to give product (7 mg, 57%). ¹H NMR (360 MHz, CDCl₃),1.22 (3H, d, J=6.9 Hz), 1.48-1.58 (2H, m), 1.74-1.96 (3H, m), 2.30-2.50(3H, br), 2.53-2.62 (1H, br), 2.71-2.81 (1H, m), 6.78-6.84 (1H, m),7.00-7.09 (2H, m), 7.30-7.37 (4H, m).

Example 95

Prepared from the ketone of Preparation 3, following the procedures ofPreparation 4 and Examples 1 and 2. ¹H NMR (360 MHz, CDCl₃) 1.52-1.61(2H, m), 1.76-1.81 (2H, m), 2.20-2.26 (1H, m), 2.39 (2H, d, J=7.6 Hz),2.40-2.50 (4H, m), 5.37 (1H, br), 5.51 (1H, br), 6.75-6.83 (1H, m),7.01-7.08 (2H, m), 7.51 (2H, d, J=8.3 Hz) and 7.64 (2H, d, J=8.3 Hz).

Example 96

Prepared from the acid of Example 95 by the procedure of Example 40,using ammonia in the second step. MS MH+ 462(463).

Example 97

Method (a)

A slurry of methoxymethyltriphenylphosphonium chloride (5.14 g, 15.0mmol) in toluene (30.0 mL) was cooled to −2° C. and t-BuOK (14.0 mL of a1M THF solution, 14.0 mmol) was added. The resulting solution wasstirred for 30 min andcis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexaneacetaldehyde(Example 87) (4.13 g, 10.0 mmol) in toluene (15.0 mL) was added. Afterthe reaction was complete, the mixture was quenched with NH₄Cl (10% aq.;30 mL) and the layers separated. The organics were evaporated to drynessand the resultant solids stirred in DMF (45 mL) with 1N HCl (7.5 mL) at45° C. After 1 hr, the solution was cooled to 28° C. and water (37.5 mL)was added dropwise. The solids were filtered and washed with DMF:water(33:67, 10 mL) and water (10 mL). Drying overnight in vacuo at 40° C.under a nitrogen stream furnishedcis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)-cyclohexanepropanal(4.04 g, 95%). ¹H NMR (CD₂Cl₂) 9.67 (1H, t, J=1.5 Hz), 7.32-7.20 (4H,m), 7.03-6.90 (2H, m), 6.82-6.70 (1H, m), 2.39-2.22 (6H, m), 1.72-1.51(4H, m) and 1.50-1.30 (3H, m).

Method (b)

To a solution ofcis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexanepropionitrile(Example 89) (627 g, 1.48 mol) in dichloromethane (3.14 L) and toluene(10.19 L) at −60° C. under nitrogen was added 1.5M diisobutyl aluminiumhydride (1.14 Kg, 2.0 mol) over 1 hour. The resulting solution wastransferred into 0.75M citric acid solution (25 L), and the bi-phasicsolution was stirred at room temperature overnight. The layers wereseparated and the organic phase was washed with 2M hydrochloric acid (17L), water (20 L), and brine (IL). Concentration to dryness providedcrudecis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexanepropanalas a white solid. ¹H NMR CDCl₃—as for Method (a).

Example 98

Method (a)

The ester from Example 86 (104 mg, 0.23 mmol) was dissolved in a mixtureof ethanol (10 ml) and water (3 ml) and stirred at 20° C. The flask wasdegassed and then lithium hydroxide (27 mg, 1.15 mmol) was added. Themixture was stirred for 3 hrs. at room temperature. 1N Hydrochloric acidwas then added and the mixture was washed with ethyl acetate (2×50 ml).The organic phase was washed with brine (50 ml), dried (MgSO₄) andevaporated. The oil obtained was then further purified by preparativetlc eluting with ethyl acetate to give the acid. ¹H NMR (CDCl₃)7.37-7.30 (4H, m), 7.09-6.99 (2H, m), 6.85-6.79 (1H, m), 2.42-2.36 (6H,m), 1.85-1.79 (2H, m), 1.73-1.69 (2H, m), 1.63-1.58 (1H, m) and1.53-1.45 (2H, m).

Method (b)

To a solution of crudecis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexanepropanal(Example 97, method (b)) (650 g, 1.52 mol) in CH₂Cl₂ (6 L) and H₂O (6 L)was added sulfamic acid (215.5 g, 2.21 mol) followed by slow addition ofsodium chlorite (180 g in 3.13 L H₂O, 2.0 mol) over 30 min. maintainingthe internal temperature below 30° C. The phases were separated and theorganic layer was washed with an aqueous Na₂S₂O₅ solution (157 g in 20 LH₂O), water (20 L) and then dried (Na₂SO₄). The solution wasconcentrated in vacuo and the residue was recrystallised fromIPAc/heptane to affordcis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexanepropanoicacid (482 g, 74%). ¹H NMR as for product of method (a).

A sample of this product (100 g, 0.226 mol) was dissolved in isopropanol(2000 mL) at 45° C. and treated with 2M aqueous sodium hydroxidesolution (112 mL, 0.224 mol). The resulting solution was distilled atatmospheric pressure to remove 1000 mL of distillate, then freshisopropanol (1000 mL) was added and the distillation process repeated.More isopropanol (1000 mL) was added and the distillation processrepeated once more. Crystallisation of the sodium salt began during thedistillation process. The reaction mixture was allowed to cool toambient temperature, aged for 1 hour and then filtered. The filter cakewas washed with isopropanol (200 mL) and then dried overnight at 40° C.in vacuo to furnish the sodium salt ofcis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexanepropanoicacid (95 g) in 91% yield.

Example 99

The acid from Example 98 (52 mg, 0.118 mmol) in dichloromethane (2 ml)was treated with oxalyl chloride (88 μl, 2 M solution indichloromethane, 0.176 mmol). A drop of N,N-dimethylformamide was addedand the solution allowed to stir for 2 hours. After this time, solventwas removed in vacuo and the residue redissolved in dichloromethane (1ml). This solution was dripped into methanolic ammonia (2 M, 2 ml). Thereaction was evaporated in vacuo and the residue chromatographed onsilica, eluting with 80% ethyl acetate in hexanes. The resultingmaterial was purified further by preparative t.l.c., eluting with 100%ethyl acetate followed by recrystallisation from hot hexane to giveproduct (7.4 mg, 14%). ¹H NMR (360 MHz, CDCl₃), 1.45-1.53 (2H, m),1.57-1.65 (1H, br), 1.70-1.75 (2H, m), 1.78-1.84 (2H, m), 2.32 (2H, t,J=15.3 Hz), 2.38-2.44 (4H, br), 2.95 (3H, s), 3.02 (3H, s), 6.79-6.86(1H, m), 7.00-7.09 (2H, m), 7.31-7.37 (4H, m); ms. (ES⁺), 470 (M⁺1), 294(M⁺175).

Example 100

The acid from Example 98 (52 mg, 0.118 mmol) in dichloromethane (2 ml)was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (45 mg, 0.235 mmol), triethylamine (32.7 μl, 0.235 mmol)and tert-butylamine (24.6 μl, 0.235 mmol). After 2 hours stirring atroom temperature, reaction was washed with hydrochloric acid (1 N, 10ml), organics dried (MgSO₄) and evaporated in vacuo to give crude (55mg). This material was chromatographed on silica, eluting with 20-30%ethyl acetate in hexanes to give product (25 mg, 43%). ¹H NMR (400 MHz,CDCl₃), 1.35 (9H, s), 1.45-1.62 (3H, m), 1.67-1.74 (2H, m), 1.76-1.80(2H, m), 2.08-2.12 (2H, m), 2.38-2.42 (4H, br), 5.72-5.78 (1H, br),6.76-6.88 (1H, m), 7.00-7.10 (2H, m), 7.31-7.37 (4H, m).

Example 101

Prepared from the ketone of Preparation 3 following the procedures ofPreparations 5-8 and Examples 54, 85, 86 and 98, method (a).

¹H NMR (360 MHz, CDCl₃) δ 10.1 (1H, m), 7.64 (2H, d, J=8.3 Hz), 7.53(2H, d, J=8.3 Hz), 7.09-7.00 (2H, m), 6.83-6.76 (1H, m), 2.50-2.37 (6H,m), 1.85-1.81 (2H, q, J=7.4 Hz), 1.75-1.70 (2H, m), 1.63-1.59) (1H, m),1.55-1.45 (2H, m). MS (EI⁺) 477 (MH⁺).

1. A compound of formula I:

wherein: m is 0 or 1; Z represents halogen, CN, NO₂, N₃, CF₃, OR^(2a),N(R^(2a))₂, CO₂R^(2a), OCOR^(2a), COR^(2a), CON(R^(2a))₂, OCON(R^(2a))₂,CONR^(2a)(OR^(2a)), CON(R^(2a))N(R^(2a))₂, CONHC(═NOH)R^(2a),heterocyclyl, phenyl or heteroaryl, said heterocyclyl, phenyl orheteroaryl bearing 0-3 substituents selected from halogen, CN, NO₂, CF₃,OR^(2a), N(R^(2a))₂, CO₂R^(2a), COR^(2a), CON(R^(2a))₂ and C₁₋₄alkyl;R^(1b) represents H, C₁₋₄alkyl or OH; R^(1c) represents H or C₁₋₄alkyl;with the proviso that when m is 1, R^(1b) and R^(1c) do not bothrepresent C₁₋₄alkyl; Ar¹ represents C₆₋₁₀aryl or heteroaryl, either ofwhich bears 0-3 substituents independently selected from halogen, CN,NO₂, CF₃, OH, OCF₃, C₁₋₄alkoxy or C₁₋₄alkyl which optionally bears asubstituent selected from halogen, CN, NO₂, CF₃, OH and C₁₋₄alkoxy; Ar²represents C₆₋₁₀aryl or heteroaryl, either of which bears 0-3substituents independently selected from halogen, CN, NO₂, CF₃, OH,OCF₃, C₁₋₄alkoxy or C₁₋₄alkyl which optionally bears a substituentselected from halogen, CN, NO₂, CF₃, OH and C₁₋₄alkoxy; R^(2a)represents H, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₆alkyl,C₂₋₆alkenyl, any of which optionally bears a substituent selected fromhalogen, CN, NO₂, CF₃, OR^(2b), CO₂R^(2b), N(R^(2b))₂, CON(R^(2b))₂, Arand COAr; or R^(2a) represents Ar; or two R^(2a) groups together with anitrogen atom to which they are mutually attached may complete anN-heterocyclyl group bearing 0-4 substituents independently selectedfrom ═O, ═S, halogen, C₁₋₄alkyl, CN, NO₂, CF₃, OH, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, CO₂H, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,carbamoyl, Ar and COAr; R^(2b) represents H, C₁₋₆alkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylC₁₋₆alkyl, C₂₋₆alkenyl, any of which optionally bears asubstituent selected from halogen, CN, NO₂, CF₃, OH, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, CO₂H, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,carbamoyl, Ar and COAr; or R^(2b) represents Ar; or two R^(2b) groupstogether with a nitrogen atom to which they are mutually attached maycomplete an N-heterocyclyl group bearing 0-4 substituents independentlyselected from ═O, ═S, halogen, C₁₋₄alkyl, CN, NO₂, CF₃, OH, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, CO₂H, amino, C₄alkylamino, di(C₄alkyl)amino,carbamoyl, Ar and COAr; Ar represents phenyl or heteroaryl bearing 0-3substituents selected from halogen, C₁₋₄alkyl, CN, NO₂, CF₃, OH,C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, carbamoyl, C₁₋₄alkylcarbamoyl anddi(C₁₋₄alkyl)carbamoyl; “heterocyclyl” at every occurrence thereof meansa cyclic or polycyclic system of up to 10 ring atoms selected from C, N,O and S, wherein none of the constituent rings is aromatic and whereinat least one ring atom is other than C; and “heteroaryl” at everyoccurrence thereof means a cyclic or polycyclic system of up to 10 ringatoms selected from C, N, O and S, wherein at least one of theconstituent rings is aromatic and wherein at least one ring atom of saidaromatic ring is other than C; or a pharmaceutically acceptable saltthereof.
 2. A compound according to claim 1 wherein Ar¹ is selected fromphenyl groups substituted in the 4-position with halogen, methyl ortrifluoromethyl, and phenyl groups substituted in the 3- and 4-positionsby halogen.
 3. A compound according to claim 1 wherein Ar² is selectedfrom phenyl groups substituted in the 2- and 5-positions by halogen. 4.A compound according to claim 1 wherein Z represents N(R^(2a))₂ and theR^(2a) groups complete an N-heterocyclyl group.
 5. A compound accordingto claim 1 wherein Z represents CO₂R^(2a) and R^(2a) represents H orC₁₋₆alkyl.
 6. A compound according to claim 1 wherein Z representsCOR^(2a) and R^(2a) represents Ar.
 7. A compound according to claim 1wherein Z represents CON(R^(2a))₂ or OCON(R^(2a))₂, and the R^(2a)groups independently represent H or optionally substituted alkyl,cycloalkyl, cycloalkylalkyl or alkenyl, or together complete anN-heterocyclyl group.
 8. A compound according to claim 1 wherein Zrepresents CON(R^(2a))(OR^(2a)) or CON(R^(2a))N(R^(2a))₂, and eachR^(2a) represents H or C₁₋₆alkyl.
 9. A compound according to claim 1wherein Z represents a 5-membered heteroaryl group.
 10. A compoundaccording to claim 5 wherein m is 1, Ar¹ represents 4-chlorophenyl, Ar²represents 2,5-difluorophenyl, R^(1b) and R^(1c) both represent H, and Zrepresents CO₂H.
 11. A compound according to claim 5 wherein m is 1, Ar¹represents 4-trifluoromethylphenyl, Ar represents 2,5-difluorophenyl,R^(1b) and R^(1c) both represent H, and Z represents CO₂H.
 12. Acompound according to claim 7 wherein m is 0, Ar¹ represents4-chlorophenyl, Ar² represents 2,5-difluorophenyl, R^(1c) represents Hand Z represents CONH₂.
 13. A compound according to claim 7 wherein m is0, Ar¹ represents 4-trifluoromethylphenyl, Ar² represents2,5-difluorophenyl, R^(1c) represents H and Z represents CONH₂.
 14. Acompound according to claim 7 wherein m is 0, Ar¹ represents4-chlorophenyl, Ar² represents 2,5-difluorophenyl, R^(1c) represents Hand Z represents CONHCH₂CH₃.
 15. A compound according to claim 9 whereinm is 0, Ar¹ represents 4-chlorophenyl, Ar² represents2,5-difluorophenyl, R^(1c) represents H and Z represents1,2,3,4-tetrazol-5-yl.
 16. A pharmaceutical composition comprising acompound of formula I as defined in claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 17.A compound of formula I as defined in claim 1, or a pharmaceuticallyacceptable salt thereof, for use in a method of treatment of the humanbody.
 18. A method of treatment of a subject suffering from or prone toa condition associated with the deposition of β-amyloid which comprisesadministering to that subject an effective amount of a compound offormula I as defined in claim 1 or a pharmaceutically acceptable saltthereof.
 19. A method according to claim 18 wherein the condition isAlzheimer's disease.